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, 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 change into impatient by the absence of any main therapeutic advances within the 25 years since L-dopa had been authorised 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 needs to be useful for understanding all types of the illness. Strategies now out there ought to enable 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 properly.
As Nussbaum had predicted, progress had occurred quickly. President Clinton in his 1998 State of the Union handle, mentioned:
“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 12 months scientists situated the gene that causes Parkinson’s illness in solely 9 days.”
The NIH is Requested to Take a Management Position
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 benefit from 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 parts of the PD group. The group’s suggestions shaped the premise of a five-year PD Analysis Agenda.
The Analysis Agenda was codified in a complete 42-page report that coated all facets of analysis from higher understanding the illness, to creating new analysis capabilities, to creating new therapies, 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 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 can 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 Route.
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 members generated greater than fifty particular suggestions. NIH thought-about these plans and the unmet objectives 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 function 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 is just not a uncommon or orphan illness, different extra prevalent ailments reminiscent of 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 present PD or different neurological medication (e.g., dopamine agonists) quite than investing in new medication.”
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 means 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, Bettering Lives. The aim of this initiative was to establish important challenges and to spotlight the very best priorities for advancing analysis.
Thirty-one suggestions have been offered. 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.
Provided 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.
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 important 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 Common Brigham and Merck— made large 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 20 years of fundamental analysis, 5 non-public 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, 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 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 combat 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 a minimum of one of many 5 on-going trials will probably be profitable, we are able to anticipate a remedy using A-syn will probably be authorised 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 utility to sufferers can 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 consequence of remaining massive gaps in information of the underlying biology that causes and drives the illness. As we fill in these gaps, the probabilities of success will improve. Among 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 assets.
In studying the PD analysis plans and stories from 2000, 2006 and 2014, it seems that NINDS threw every part it knew about PD into the hopper. There have been tons of of suggestions, initiatives and so-called priorities. However a key issue of success in analysis is having a workforce of motivated scientists with the mandatory expertise, information and pondering skill to unravel a finely-honed query.
There merely aren’t sufficient nice minds to trace down the entire “to do’s” within the three NINDS PD analysis plans. Additionally, communications and networking are necessary parts 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 project 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 have 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 drawback in crossing the Valley of Dying from fundamental analysis to scientific trials, however these organizations fell again to their consolation zone, particularly small grants to academicians. This technique didn’t produce the mandatory outcomes.
A Higher Method
In 1998 and thereafter, alpha-synuclein wanted a swat workforce of top-flight researchers together with a dedication for extra funds because the undertaking progressed out of fundamental analysis and thru the requisite scientific trials.
To deal with the shortcomings to this point, the Division of Well being and Human Companies (HHS) ought to step in and 1) slim the PD analysis precedence checklist 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 area.
Specifically, HHS/NIH/NINDS should acknowledge that investments in new healthcare therapies reminiscent of 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 reminiscent of A-syn. The outcome has been a Valley of Dying between fundamental analysis and drug improvement. Second, even when the preliminary Valley could be crossed by means of authorities grants or non-profit donations, the FDA regulatory scheme places an infinite burden on firms to lift scores of thousands and thousands of {dollars} for prolonged scientific trials that face an unsure regulatory final 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 educational entrepreneur, early improvement of an efficient regulatory plan could be the distinction between success and failure. Due to this fact, 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 in the case of 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 needs 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 needs 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 incorporates deceptive info.
Facilitating common exchanges of data, knowledge sharing, and collaboration ought to assist to maximise the affect of analysis efforts and keep away from duplication of labor. For the funding group, a partition within the hub with investment-related info 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 (quite 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 contemplate 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 establish the three most-likely-to-succeed paths to a remedy. It ought to be certain that these paths have enough personnel and ample analysis {dollars} for completion. Progress needs to be monitored regularly.
Lastly, I ought to point out that the Michael J. Fox Basis has carried out a wonderful job on a variety of necessary points and needs to 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 every one parts 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 assets whether or not or not it’s with alpha synuclein or different therapies. Such has not been the case with A-syn to this point, and equally, we have now 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 examine tracks the decades-long journey to harness alpha-synuclein as a therapy for Parkinson’s illness. The writer 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 change into impatient by the absence of any main therapeutic advances within the 25 years since L-dopa had been authorised 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 needs to be useful for understanding all types of the illness. Strategies now out there ought to enable 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 properly.
As Nussbaum had predicted, progress had occurred quickly. President Clinton in his 1998 State of the Union handle, mentioned:
“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 12 months scientists situated the gene that causes Parkinson’s illness in solely 9 days.”
The NIH is Requested to Take a Management Position
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 benefit from 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 parts of the PD group. The group’s suggestions shaped the premise of a five-year PD Analysis Agenda.
The Analysis Agenda was codified in a complete 42-page report that coated all facets of analysis from higher understanding the illness, to creating new analysis capabilities, to creating new therapies, 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 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 can 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 Route.
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 members generated greater than fifty particular suggestions. NIH thought-about these plans and the unmet objectives 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 function 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 is just not a uncommon or orphan illness, different extra prevalent ailments reminiscent of 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 present PD or different neurological medication (e.g., dopamine agonists) quite than investing in new medication.”
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 means 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, Bettering Lives. The aim of this initiative was to establish important challenges and to spotlight the very best priorities for advancing analysis.
Thirty-one suggestions have been offered. 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.
Provided 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.
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 important 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 Common Brigham and Merck— made large 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 20 years of fundamental analysis, 5 non-public 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, 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 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 combat 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 a minimum of one of many 5 on-going trials will probably be profitable, we are able to anticipate a remedy using A-syn will probably be authorised 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 utility to sufferers can 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 consequence of remaining massive gaps in information of the underlying biology that causes and drives the illness. As we fill in these gaps, the probabilities of success will improve. Among 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 assets.
In studying the PD analysis plans and stories from 2000, 2006 and 2014, it seems that NINDS threw every part it knew about PD into the hopper. There have been tons of of suggestions, initiatives and so-called priorities. However a key issue of success in analysis is having a workforce of motivated scientists with the mandatory expertise, information and pondering skill to unravel a finely-honed query.
There merely aren’t sufficient nice minds to trace down the entire “to do’s” within the three NINDS PD analysis plans. Additionally, communications and networking are necessary parts 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 project 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 have 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 drawback in crossing the Valley of Dying from fundamental analysis to scientific trials, however these organizations fell again to their consolation zone, particularly small grants to academicians. This technique didn’t produce the mandatory outcomes.
A Higher Method
In 1998 and thereafter, alpha-synuclein wanted a swat workforce of top-flight researchers together with a dedication for extra funds because the undertaking progressed out of fundamental analysis and thru the requisite scientific trials.
To deal with the shortcomings to this point, the Division of Well being and Human Companies (HHS) ought to step in and 1) slim the PD analysis precedence checklist 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 area.
Specifically, HHS/NIH/NINDS should acknowledge that investments in new healthcare therapies reminiscent of 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 reminiscent of A-syn. The outcome has been a Valley of Dying between fundamental analysis and drug improvement. Second, even when the preliminary Valley could be crossed by means of authorities grants or non-profit donations, the FDA regulatory scheme places an infinite burden on firms to lift scores of thousands and thousands of {dollars} for prolonged scientific trials that face an unsure regulatory final 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 educational entrepreneur, early improvement of an efficient regulatory plan could be the distinction between success and failure. Due to this fact, 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 in the case of 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 needs 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 needs 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 incorporates deceptive info.
Facilitating common exchanges of data, knowledge sharing, and collaboration ought to assist to maximise the affect of analysis efforts and keep away from duplication of labor. For the funding group, a partition within the hub with investment-related info 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 (quite 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 contemplate 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 establish the three most-likely-to-succeed paths to a remedy. It ought to be certain that these paths have enough personnel and ample analysis {dollars} for completion. Progress needs to be monitored regularly.
Lastly, I ought to point out that the Michael J. Fox Basis has carried out a wonderful job on a variety of necessary points and needs to 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 every one parts 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 assets whether or not or not it’s with alpha synuclein or different therapies. Such has not been the case with A-syn to this point, and equally, we have now 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 internet utility and internet hosting enterprise when he was identified 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
