Articles

Newsletter Winter 2020

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Note from Kinexum CEO
Thomas Seoh
 
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Dear Friends of Kinexum,

This Winter 2020 edition of Kinexions, the Kinexum newsletter, includes:
 
(1) a personal report on our October Targeting Metabesity 2019 conference (which an observer called “one of the most important longevity conferences of the year”) by Michael Zemel, PhD, Founder and CSO of NuSirt BioPharma, a speaker in the Emerging Companies session;
 
(2) my interview of Faiez Zannad, Professor of Therapeutics and Cardiology and Director of the Inserm Clinical Investigation Centre at the University of Lorraine in Nancy, France, and a co-organizer of the uncommonly influential 
Cardiovascular Clinical Trialists Forum, December 5-7, 2019 in Washington, DC, for which Kinexum has helped to organize a Rare Disease Workshop on Thursday, December 5, from 3:30 p.m. to 7 p.m. (see the program here); and
 
(3) an article on how photobiomodulation may be a solution for the opioid crisis, based on his Kinexum webcast of October 25, 2019 (see 
recording and slides), by James Carroll, CEO of THOR Photomedicine Ltd.
 
There is also a second installment of autobiographies by Kinexum consultants, on which Zan comments in his column.
Read More
 
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Reflections on Targeting Metabesity 2019

Michael B. Zemel, PhD
It’s been over a month now since Targeting Metabesity 2019 (“M19”) wrapped up, giving me some time to reflect on meeting takeaways and integrate them into my own thinking and practice.

“Metabesity,” a term coined by Zan Fleming and the centerpiece of M19, reflects the notion that there is a common root cause to cardiometabolic disease, neurodegenerative disease, and cancer, and re-casts these conditions as a constellation of interconnected diseases with common causation that overlaps or is identical with the etiology of degenerative aging.
 
What I offer in this article is a rather subjective, personal view and editorial comments of the conference, rather than detail of all the sessions and speakers. If you were unable to attend the meeting and would like to see a factual summary, I encourage you to view the highlights
 here
and/or view the videos of most talks and panels on the Kinexum YouTube channel.
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Why Photobiomodulation Might be the Answer to the Opioid Crisis

James Carroll

Disclosure: James Carroll is Founder & CEO of THOR Photomedicine Ltd, as well as Co-founder of and Investor in Lumithera, Inc.

The opioid crisis
You probably do not need much reminding about America’s opioid crisis; the numbers are huge. CDC figures state that there are 100 million adults in the United States (US) affected by chronic pain, and over $600 billion a year are spent on health care costs related to pain and lost productivity. There were over 49,000 deaths associated with opioids in 2017—19,000 of which came from prescribed opioids.

According to the Assistant Secretary for Health, Admiral Brett Giroir, “you cannot solve the opioid crisis without solving the pain crisis” [1].

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From Kinexum Founder
Zan Fleming, MD
 
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Dear Kinexum friends and family,

As 2019 closes with a welcomed season of rest, re-creation, and celebration with family, friends, and colleagues, I am struck by what the Kinexum community has achieved this year in fulfilling a driving aspiration.
 
The name “Kinexum” reflects that founding objective—to connect people with shared goals to solve important challenges. The Greek and Latin cognates, kine and nexum, express the “how” and the “what” of our society. Kine means “energy,” which is an important attribute of how Kinexum works—applying intensity, accountability, and velocity to its craft. Nexum, from connexio, literally means “binding together.” In our context, the intended meaning is binding together people, ideas, and shared goals. Binding together—connecting—people, is the most important intent of all.

And, what a marvelous year Kinexum has had in doing that under Thomas’ leadership. Kinexum has added distinguished experts to our core group; it has formed new strategic relationships with other organizations and strengthened established ones. Kinexers have catalyzed initiatives, which have brought scholars and new ideas together. Kinexum has sponsored conferences and other gatherings, which have resulted in friendships, publications, and other collaborations...
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Interview with Professor Faiez Zannad on the Cardiovascular Clinical Trialists Forum

Faiez Zannad, MD, PhD, FESC
In this feature, Faiez Zannad, Professor of Therapeutics and Cardiology and Director of the Inserm Clinical Investigation Centre at the University of Lorraine in Nancy, France, interviewed with Thomas Seoh about the 16th Cardiovascular Clinical Trialists Forum (CVCT), which will be held on December 5–7, 2019, in Washington, DC.

Thomas Seoh: Many thanks, Faiez, for agreeing to do this interview. Let's start off with: what is the focus of this conference?
 
Faiez Zannad: The Cardiovascular Clinical Trialists Forum is designated by its name. It is focused on cardiovascular clinical trials. However, “cardiovascular” has now expanded to fields like cardiorenal and cardiometabolism, so anything related to cardiovascular, including kidney diseases, diabetes, or other diseases with cardiovascular outcomes, is the focus of this meeting.

 
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Another Immigrant's Tale

Thomas Seoh
We were all shocked earlier this year by the sudden loss of Kinexer Lana Pauls to a fatal accident. Zan instituted this feature in our newsletter to highlight personal biographies of Kinexers, so we could learn a little about each other beyond our roles as consulting professionals, before reading them in some obituary. When I was reading Mustafa Noor’s remarkable tale of his journey from war-torn Afghanistan to America, I never thought I would draw the second personal biography assignment.
 
I, too, am an immigrant, though my journey has been nowhere as dramatic as Mustafa’s. The major steps had been taken by my parents: my father was born in a small southern port town in Korea, my mother a couple towns over. In their lifetimes, they made the leap from essentially 19th century agrarian Korea to the late 20th century first world of Seattle, Singapore, London, and Honolulu. 
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Metabesity 2019 Update
Targeting Metabesity 2019, held on October 15–16, 2019, at the Carnegie Institute for Science in Washington, DC, was a resounding success. Following the conference, Kinexum held a company retreat located in Harpers Ferry, WV.

Below are a few photos from the memorable week. For more photos, as well as recordings of the conference, visit 
http://www.metabesity2019.com.
Zan at Targeting Metabesity 2019
Keynote Speakers Drs. Richard Hodes and Janet Woodcock
Dr. Nir Barzilai, Jamie Metzl, Dr. Leonard Guarente, and Dr. David Sinclair
Kinexum Retreat at Harpers Ferry, WV
Kinexum Retreat at Harpers Ferry, WV
 
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Upcoming Webcasts
December Kinexum Webcast
Kinexum’s December webcast features Jinhui Dou, PhD, Kinexum pharmacology and pharmacognosy senior consultant. Dr. Dou will speak on “Tea, Dragon’s Blood, Cannabis, and Ginseng: Herbal Medicine, Dietary Supplements, or Botanical New Drugs?”

Dr. Dou will provide an overview of these substances and how botanical drugs are developed and regulated in the United States. 


Click here to RSVP
 
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New Kinexum Team Members

 

Jinhui Dou, PhD

Jinhui Dou, PhD
Pharmacology and Pharmacognosy Senior Consultant

Steven Grossman, JD
Regulatory and Government Affairs Senior Consultant
 
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Upcoming Conferences

Kinexum executives and leading experts will attend the following conferences. If you are interested in meeting with a Kinexum representative at these conferences, please contact  This email address is being protected from spambots. You need JavaScript enabled to view it. .
 
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Advanced Technologies & Treatments for Diabetes 2020
 
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Immunology of Diabetes Society 2020
 
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Recent Publications
 
A Regulatory Pathway for Medicines That Target Aging
G. Alexander Fleming, Jennifer H. Zhao, Thomas C. Seoh, and Nir Barzilai
Public Policy & Aging Report (September 2019)


Culinary Medicine: Advancing a Framework for Healthier Eating to Improve Chronic Disease Management and Prevention
Irl B. Hirsch, Alison Evert, Alexander Fleming, Linda M. Gaudiani, Karl J. Guggenmos, Daniel I. Kaufer, Janet B. McGill, Carol A. Verderese, Joe Martinez
Clinical Therapeutics (October 2019)


To help aging populations, classify organismal senescence
Stuart R. G. Calimport, Barry L. Bentley, Claire E. Stewart, Graham Pawelec, Angelo Scuteri, Manlio Vinciguerra, Cathy Slack, Danica Chen, Lorna W. Harries, Gary Marchant, G. Alexander Fleming, Michael Conboy, Adam Antebi, Gary W. Small, Jesus Gil, Edward G. Lakatta, Arlan Richardson, Clifford Rosen, Karoly Nikolich, Tony Wyss-Coray, Lawrence Steinman, Thomas Montine, João Pedro de Magalhães, Judith Campisi, George Church
Science (November 2019)


The Need to Change Regulatory Evaluation of Hypoglycemia in Trials of Diabetes Treatments
David C. Klonoff, Alexander Fleming, and Robert Gabbay
Journal of Diabetes Science and Technology (November 2019)


Diabetes digital app technology: benefits, challenges, and recommendations. A consensus report by the European Association for the Study of Diabetes (EASD) and the American Diabetes Association (ADA) diabetes technology working group [link becomes available on December 4, 2019]
G. Alexander Fleming, John R. Petrie, Richard M. Bergenstal, Reinhard W. Holl, Anne L. Peters, and Lutz Heinemann

Diabetologia and Diabetes Care (December 2019)
 
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Continuation of Previous Articles
Note from Kinexum CEO (cont.)

This past quarter saw the release of several new publications co-authored by Kinexum consultants:
Zan also moderated a panel, and urged hypoglycemia to be adopted as a clinically important endpoint, during the Diabetes Technology Meeting (November 14-16, 2019) in Bethesda (see photo below).

Zan at DTM 2019

In addition to the CVCT Forum in Washington, DC December 5-7, 2019, Kinexum will be attending the JP Morgan healthcare week in San Francisco January 12–16, 2020, including the Biotech Showcase. We’d love to meet up with friends and colleagues, clients, and potential clients. Please email  This email address is being protected from spambots. You need JavaScript enabled to view it.  if we should try to get together, or if you would like a coupon code for 20% off the Biotech Showcase.
 
Happy reading, and best wishes for the year-end holidays and a healthy, productive, and meaningful 2020!

Cheers,

Thomas 
 
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From Kinexum Founder (cont.)
 
...Targeting Metabesity 2019 (“M19”) was successful beyond all expectations in connecting people of striking professional diversity. Expect to hear soon about important results of M19. Another unique, prestigious conference—the 16th Global Cardiovascular Clinical Trialists (CVCT) Forum—begins tomorrow, December 5. Kinexum was asked to organize a workshop within CVCT on trials for orphan conditions. CVCT is distinguished by the collegiality of the proceedings and the exceptionally high representation of FDA and other global regulatory experts who participate. Our workshop will be no different.
 
As a reflection of being a connected people, we continue our series, which highlights the life story of a Kinexer. You will be astonished by the story of Thomas Seoh. In his article, Thomas mentions that he and I met at a Kinexum-organized conference in honor of our shared mentor, Leigh Thompson, who was a beloved force of nature in the drug development world. Leigh’s interests and talents ranged far outside of pharma. He was very simply a “renaissance man.” The official name of those two conferences held in Leigh’s cherished Charleston both before and after his death was the Leigh Thompson Renaissance Conference. Here’s the point: Thomas is every bit a Renaissance man. But, brilliant, multi-talented people are often mixed bags in how they relate to family, friends, and colleagues. Thomas is as gifted in his relating to others as he is in many other ways. Thomas is always genuinely kind and attentive to others. His most treasured gift and highest priority is his beautiful family—wife Patricia, two daughters, and three sons, each exceptional in their own ways. Thomas is also the personification of kine. Getting on one call after another during the day and pounding out messages, insights, and essays well after midnight, Thomas just keeps going. And, Kinexum is so much the better for it.
 
To your health!

–Zan
 
 
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Reflections on Targeting Metabesity 2019 (cont.)

 
Overview of the conference
Most conferences have a buffet-like feel to them. You sample a bit of this session and a bit of that session, then retreat to the hallways and lounges to conduct the “real” science and business you came for. 
 
Not so for M19—not at all. Clearly emphasizing quality over quantity, this conference brought together approximately 150 active, engaged leaders—strikingly, the audience was as densely packed with key leaders as the speaker roster—from academia, industry, and government to spend two highly interactive days addressing aging as a treatable condition and taking a deep dive into both lifespan and healthspan research, clinical applications, policy, and business opportunities. In essence, much of the conference took on the feeling of a spirited roundtable discussion.
 
Although not the direct topic of much discussion per se, but worth a brief comment, the conference was launched with the release of the analytical report, “
Metabesity and Longevity: USA Special Case Study,” produced as a collaboration between the M19 team and Aging Analytics Agency. This report sets the stage for post-meeting marching orders. The report highlights the gap between US health expenditures and health-adjusted life expectancy (HALE)—we spend more than most, but our return on investment is mediocre, at best. Though the news is depressing (but perhaps obvious), a roadmap is provided in the report to move us from a “sick care economy” to one built on a combination of prevention and precision health, narrowing the HALE gap and reaping an economic longevity dividend. Much of the science is already here; we just need a combination of public, industry, and government commitment to implement. There is too much to detail here, so please download this open-access report.
 
Day 1
Day 1 of the conference focused primarily on geroscience, with back-to-back keynotes from Richard Hodes (Director of the National Institute on Aging) and Janet Woodcock (Director of FDA Center for Drug Evaluation and Research). 
 
Dr. Hodes’ talk provided a much-needed reminder that we already have some low-hanging fruit in the form of simple lifestyle interventions that can extend HALE: 
  • The LIFE study shows that a simple exercise program results in substantial reduction in the risk of major mobility disability in vulnerable, elderly populations.
  • Active cognitive training shows meaningful, long-term benefit in reasoning, speed of cognitive processing, and improvements in activities of daily living over 10 years.
  • Encouraging evidence shows that a combination of cognitive training, blood pressure management, and increased physical activity can prevent or slow age-related cognitive decline, and additional data from the SPRINT-MIND study show that intensive blood pressure control lowers the rates of mild cognitive impairment and all-cause dementia. 
These examples, plus the recent observation that healthy lifestyle is associated with lower dementia risk regardless of level of genetic risk, remind us of the low-tech/low-cost interventions we can implement today even as we await a generation of therapeutics directed against the hallmarks of aging and their underlying causes. 
 
The latter case, of course, was the subject of much of the rest of the day. Dr. Hodes introduced it by showing the development of geroscience as a discipline, progressing from studying chronic diseases individually or as clustered groups to the convergence of our understanding of the biology of disease and biology of aging into the unified discipline of geroscience. From where I stand, that framework looks a lot like the description of metabesity; while not identical, the two frameworks are very closely aligned.
 
Cellular senescence (and the development of therapeutic senolytics) was one of several recurring themes of the day, and with good reason. We know that targeting senescent cells can attenuate or reverse multiple components of metabolic dysfunction associated with aging and can extend lifespan in experimental animals, and a couple of small clinical studies have shown similar promise. 
 
There is no doubt we will seeing more on this, but let’s not forget that aggressive targeting of any pathway, even one so strongly associated with the ravages of aging, has a potential downside. As a quick example, Richard Hodes pointed out a positive side to senescent cells: they have a key role in wound healing, and clearing of senescent cells results in delayed healing. Are there other functions that would be causes for concern with aggressive targeting of senescent cells in normal aging? And how do we think about safety and unintended consequences of targeting the fundamental hallmarks of aging discussed later in the day? 
 
Perhaps there is something to learn from metformin, as highlighted by Nir Barzilai’s discussion of the TAME (Targeting Aging with Metformin) study (more on that later). Metformin holds promise to address fundamental mechanisms of aging and multiple clinical endpoints. It also has an enviable safety record, deeming it appropriate to evaluate in the prevention paradigm of the TAME study. 
 
I think it is reasonable to argue that metformin’s shortcoming—its relative weakness—is precisely what makes it a good drug, creating a bit of a paradox. In other words, its safety likely derives from the fact that it does not strike its targets with a sledgehammer that produces multi-fold changes, but instead operates as a relatively fine tool to physiologically modulate a fundamental servomechanism, minimizing the likelihood of counter-regulatory responses and resultant adverse events. Of course, this is not a new concept—it is applied in the development of every new drug, but this idea needs re-emphasis in any discussion of developing new preventive therapeutics with intended broad application to currently healthy individuals. 
 
If we did have a drug to prevent aging and/or age-related disease(s), would there be a regulatory pathway to approval? FDA’s Dr. Woodcock tells us yes, but it’s not an easy path. At this juncture, it is filled with more questions than answers, but, hopefully, we will see that change as the first candidates seeking a path forward are presented to FDA. 
 
Prevention is a big hill to climb for any disease (which explains why vaccines stand out as the single major example of approved drugs for prevention of any indication). The major reason for why prevention is difficult to prove is that it involves exposure of a large number of people over an extended period of time to an intervention designed to prevent a disease that any given individual may not progress to, bringing us back to an emphasis on the safety issue noted above. 
 
Nonetheless, aging is unavoidably different. Aging has an element of universal exposure, and the only current escape from it (which is death) is unacceptable. As Hank Williams sang, “No matter how I struggle and strive, I’ll never get out of this world alive”; we’re all aligned in our real motivation to seek alternative preventive strategies. 
 
In this context, Dr. Woodcock believes that FDA could approve a drug to prevent aging, or at least age-related disease, using a composite set of hard endpoints of equal gravity, such as myocardial infarction, MACE, cancer, dementia onset, hospitalization, and death. However, she also left room for softer measures that people care about as they age, such as avoidance of hospitalization and/or nursing home, stabilization of diabetes, maintenance of mental acuity, and a measure that enable individuals to maintain active, engaged lives without medical disruptions as they age. These are important, achievable outcomes to assess, but they are also tremendously time- and resource-intensive.
 
Are there surrogate biomarkers that can be employed as an alternative? Here, the news is a bit disheartening. Dr. Woodcock says, “It is unlikely that FDA would approve a preventive indication for a broad population based on a composite of a lot of metabolic biomarkers.” A bright spot, however, is Dr. Barzilai’s re-purposing of metformin for pan-aging prevention in the aforementioned TAME trial using a composite endpoint study (cardiovascular disease, cognitive impairment, cancer, and death) that was constructed with FDA input.
 
This point takes me to a comment that Brian Kennedy (Director of the Centre for Healthy Ageing at the National University Health System of Singapore) made in a subsequent session. Given the difficulty in identifying and reaching an approvable endpoint for prevention, perhaps it’s time to take the dietary supplement approach. Despite the unsupported noise in that space, aging presents a good opportunity to “work with the supplement market and inject science into it.” With careful selection of claims to avoid the trap of overstatement that bedevils the supplement market, I couldn’t agree more.
 
Dr. Kennedy focused his comments on the “crossroads between aging and metabolism,” pointing out that both behavioral- and small molecule-based interventions for aging and lifespan are strongly linked with and affect metabolism—once again, sounding very much like the definition of metabesity. 
 
Dr. Kennedy was joined by other geroscience luminaries. David Sinclair (Harvard University) focused on the theory of aging and echoed many of the points made in his recently released (and now best-selling) popular book, Lifespan—Why we age, and why we don’t have to. Matt Kaeberlein provided an update on—and made a compelling case for—his work using pet dogs as a bridge between model organisms and people. His Dog Aging Project could enable answers in companion animals that exhibit genotypic and phenotypic diversity and share our environment and much of our aging trajectory in a manageable period of time (e.g., 3-5 years). While his initial work focuses on rapamycin in the TRIAD (Trial of Rapamycin in Aging Dogs) trial, studying other interventions (e.g., metformin, NAD+, etc.) in companion animals could well provide more translatable solutions than the current NIA-funded intervention testing programs. 
 
It’s difficult to talk about geroscience without mentioning Leonard Guarente (MIT, and co-founder of Elysium Health) for his primary leadership and contributions to our understanding of sirtuins, sirtuin activators (STACs), and NADin aging. However, his talk at M19 quickly moved on from this topic to address solutions to specific components of aging, especially development of therapeutics for muscle maintenance during aging to prevent and treat sarcopenia and frailty. This was less of a major discussion point at M19 compared to major degenerative diseases of aging and Western lifestyle, but nonetheless critical to healthy, independent living and potentially an important endpoint to any aging intervention. I look forward to aggressive translational development of this work.
 
Going back to “low hanging fruit,” nutrition was featured prominently over both days as the best currently accessible “technology” to extend both lifespan and healthspan. Kris Verburgh (Free University of Brussels and Longevity Vision Fund) introduced us to “nutrigerontology.” Jennifer Ligibel (Dana-Farber Cancer Institute) presented an overwhelmingly convincing case for the role of weight management in cancer prevention and control. As a Day 2 keynote speaker, Susan Mayne (Director of FDA Food Safety and Applied Nutrition) highlighted improved tools to enable consumers to better understand and manage their dietary choices. There is too much to unpack in detail here, save to say that Dr. Verburgh’s approach stands in conscious contrast with established “official” dietary recommendations, which he deems (and I agree) inadequate.
 
Day 2
Day 2 shifted the focus to applications of the science mentioned in Day 1. 
 
Gary Gibbons (Director of NHLBI) set the stage in a keynote extending the translation of discovery science beyond clinical assessment to successful implementation and real-world practice. He provided key insights that one’s zipcode modifies one’s health trajectory—essentially the interplay of social and biological systems in disease prevention as seen through the lens of access to care, access to safe environments that support routine physical activity, and access to healthy, affordable foods, all of which have direct, measurable effects on the microbiome and whole-body metabolism. Going back to nutrition once more, the DASH (Dietary Approaches to Stop Hypertension) diet exhibits efficacy comparable to approved drugs for lowering blood pressure, with subsequent data demonstrating salutary effects on the metabolome and overall cardiometabolic risk. This diet is substantially similar to the Mediterranean Diet, with its emphasis on fresh fruit, vegetables, whole grains and fibers, fish and sparing use of animal protein. However, access to such a diet is linked to both geography and socioeconomic status and affect healthspan trajectory. This presents a very real opportunity for intervention accessible to us today.
 
Finally, a few takeaways from an extraordinary panel of leaders of established companies in industry as moderated by Joe Cook, Jr (Executive Chairman of NuSirt). Joe set the tone with an important challenge to act at the nexus of cost-effectiveness and healthspan extension. Steven Gough (SVP & Global CMO of Novo Nordisk) followed up and provided an overview of breadth of application of Novo’s GLP-1 portfolio in age-related disease. While this portfolio was clearly developed from a diabetes-centric perspective, and acknowledging the fact that GLP-1 dysfunction is not a primary cause of aging, the clinical data on obesity, NASH, and cardiovascular outcomes, coupled with preclinical data suggestive of benefit in neurodegenerative disease, certainly suggested pan-aging therapeutic potential. 
 
Another speaker in this panel provided an important food industry perspective, setting up an interesting contrast with comments made the previous day by Kris Verburgh (who placed the food industry at substantial blame for the obesity epidemic). In this session, Antonio Tataranni (CSO and SVP of Life Sciences at PepsiCo) began to take up that challenge. Dr. Tataranni joined PepsiCo—after a long career in drug development—out of frustration of how untreatable the problem of metabolic disease was from an economic perspective. His comments were an unexpected breath of fresh air from the food industry in outlining a new focus on health extension and nurturing vitality through diet and exercise. He outlined a framework for addressing weight, heart health, muscle function, and cognition. While there is much to be done to demonstrate that large food companies are committed to contributing to the solution rather than the problem, PepsiCo alone reaches 1–1.5 billion consumers daily. If PepsiCo embraces this call to action, it certainly has the reach to implement it.
 
There were many other truly outstanding talks I have not touched on due to space limitations. The combination of available current approaches to slow aging, rapidly emerging near-term pharmacological and consumer-facing interventions to further delay (and possibly halt) aging pathologies, commitment of established companies to address healthspan, and a guardedly optimistic regulatory view all leave hope for rapid advancement and implementation. Now I’m looking forward to seeing updates in the science and translation in this field at Targeting Metabesity 2020

Written by Michael Zemel, PhD, CSO of NuSirt Biopharma
 
 
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Interview with Professor Faiez Zannad on the Cardiovascular Clinical Trialists Forum (cont.)

 
“Trialists” refers to clinical trials. We look at clinical trials from all aspects, from methodology design to operations, as well as statistical interpretation, generalizability, approvability by regulators, and influence on clinical practices, guidelines, and reimbursement. There is no other meeting like this one.
 
Covering all these different aspects of clinical trials explains a unique feature of this meeting: bringing together various stakeholders. We have not only major principal investigators (PIs), but statisticians, methodologists, and regulators from the European Medical Agency (EMA) and US Food and Drug Administration (FDA). In fact, we now hold this meeting in Washington, DC, because of its proximity to FDA.
 
Also at this meeting is another important group of stakeholders: patients. We have “patient trialists,” who not only work within patient advocacy groups, but are involved in clinical research. Some even work with FDA and the EMA. 
 
We also have payers. Some are from the public sector, including Medicare and Medicaid of CMS. Others are from private insurances and health technology assessments from Canada and Europe. Payers are important because we consistently hear about companies with issues in getting their medication approved, as well as bigger issues on getting their medication or device reimbursed. The evidence they need for approval may not necessarily be the same as that for reimbursement. On a number of occasions, this meeting has helped align regulators' and payers' requirements.
 
Other important stakeholders are journalists and journal editors, including editors of the New England Journal of MedicineCirculationEuropean Heart Journal, and JACC. They do come to network and attract publication of a big trial in their journal, but they also explain the statistical rules for publishing trials and how to report trial results. This is important because you can have drugs and devices approved, but the results can be difficult to publish because the rules for publication can be more rigid.
 
In a nutshell, CVCT is unique because of the multiplicity of stakeholders, all of whom focus on clinical trials, even the next generation of trials like evidence-based cardiovascular medicine.
 
Thomas: The varying stakeholders and senior level of folks you’ve gathered are impressive. This is the 16th edition coming up in December, and it's at a very unique venue, the French Embassy. How many people show up?
 
Faiez: Well, the meeting used to be in France. FDA and National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH), another stakeholder I didn’t mention but is instrumental in funding clinical trials, requested that it be moved to Washington, DC. 
 
The French Embassy is a great setting and can hold up to 500 people. One of the three theaters has a particularly exceptional ambience because it feels homely, completely different from meetings in major ballrooms or typical hotels. It allows people to network more easily.
 
Every year, we have 400–500 attendees. These are top-notch people all involved in clinical trials. One out of three people are faculty, which includes people from research and development directors and chief medical officers from industry. These people also come to interact with other stakeholders. Furthermore, every session has industry speakers. 
 
When we say this meeting takes on a multi-stakeholder approach, we mean it. Every kind of stakeholder sits on a panel and participates as a speaker.
 
Thomas: Let's focus specifically on the CVCT taking place this coming December 5­–7. Could you highlight any particular features or themes covered by this conference? 
 
Faiez: There are so many. Each day, there will be three parallel sessions, with six or seven total sessions per day. 
 
One major feature is a session with NIH on implementation science. Even though great evidence is produced for medications, the real-life use of these data is subpar, so we need to pay attention to how to implement the results of clinical trials. This session will cover implementation trials using electronic health records and implementation methods embedded in healthcare systems around the world.
 
Another feature is a session on real world evidence. Real world evidence is being increasingly used for approvals or post-approvals. It brings its own challenges and opportunities, especially with respect to digital health and how much it can help in clinical trials.
 
Of course, we’ll have sessions on disease-specific areas. There will be sessions on SGLT2 inhibitors, the PARAGON trial, heart failure, ischemia, and other cardiovascular indications. This will be the time to learn from case studies and assess how far we’ve come.
 
This year, we started a new initiative called interventional CVCT (ICVCT), where we have a full day of trials in the interventional cardiology area. The interventional cardiologists have come up with proof of evidence. It's important to get them within this multi-stakeholder setting.
 
There will be a rare disease workshop, which Kinexum helped design. This is very new and something we are proud of. CVCT has mainly been focused on large trials, since the numbers for cardiovascular disease are large, but we don't know how to do small trials. We’ve become increasingly interested in rare disease, so now we have a session where rare disease and cardiovascular diseases trialists can learn from each other.
 
We are also attracting oncologists to this year’s meeting. Oncology trials are different from cardiovascular trials, and many people say that the bar to oncology approvals is low but has become high in cardiovascular. We want to figure out how to strike a balance. Oncology and cardiovascular trialists will meet, and we will also have the oncology and cardiovascular divisions of FDA present.
 
Overall, this is going to be a very interesting dialogue.
 
Thomas: What are some memorable learnings or experiences that have stuck with you from previous CVCT Forum meetings?
 
Faiez: One thing we take pride in is having moved the line for a couple of issues. For example, we got better alignment between payers and regulators in setting the stage for what can be approved and what can be reimbursed. Most heart failure trials are mortality trials, but there have been many trials that have paved the way for improving quality of life. We discussed at CVCT how important was it to improve quality of life, short of necessarily prolonging life. Payers were also part of the evaluation, commenting on how much they can value an increase in quality of life score or increase in walk distance, short of any improvement in mortality. What came out of the discussion was reissuance of FDA guidance and approval of the Kansas City Cardiomyopathy Questionnaire (KCCQ).
 
Another thing is how we’ve emphasized the role of patients in encounters between regulators and investigators. CVCT is where regulators and investigators can come and learn from patients. Now, FDA has embedded patients into its boards.
 
A third thing is the position papers we write. If you search “CVCT” in Google Scholar, you can find papers that highlight the important discussions we’ve had. Some of these papers are even drafted by young investigators mentored by senior investigators. 
 
It’s worth mentioning that CVCT is engaged in supporting young investigators. Fewer and fewer cardiologists are getting into clinical research, so we work to engage young investigators. Every year, we award 40–50 young investigators full grants to attend the meeting, and we have courses with them on statistics and best practices to apply for and get NIH funding. This year, we will have shark tanks, where a young investigator will pitch their trial and win the opportunity to be mentored by a big-name PI. 
 
Recently, FDA talked to us about increasing the number of investigators from ethnic minorities. In the US, the number of African Americans, Hispanics, and other minority patients in trials is very low. The extrapolation of results of clinical trials to Americans is dangerous because most Americans are from ethnic minorities and are not accurately represented in trials. At CVCT, we came up with the idea that the best way to enroll patients from ethnic minorities is to have more ethnic minority investigators. Thus, we are trying to attract more young investigators from ethnic minorities and encourage them to become full investigators. Hopefully, this will diversify patient participation.
 
Thomas: Very interesting. Looking towards the future, what do you hope for? What do you see as important issues that the forum will address over the next three to five years?
 
Faiez: We want to expand the mindset of the meeting and make it a think tank. For example, talks in each session are limited to 5–10 minutes, and they are followed by two to three hours of discussion. We instruct our speakers to not lecture, since everyone in the room is knowledgeable about the topic, but to bring up the issue and discuss it with all the stakeholders. 
 
This kind of interaction can’t happen in large ballrooms with hundreds of people sitting around. We favor smaller interactions, so we have created spin-off meetings. We have held a CVCT in Asia for the past five to six years, which addresses the same issues but for the Asian market, investigators, and regulators. We also have a Mediterranean, Middle East, and Africa (MEMA) CVCT in Cairo. We try to apply the same kind of mindset to these different regions of the world with different regulatory issues and healthcare systems.
 
We also want to diversify meetings themes. As I mentioned, cardiovascular is something seen in other disciplines like diabetes, renal diseases, and intensive care, so we hold other meetings focusing on those fields. One meeting is Kidney Disease Clinical Trialists (KDCT), which my colleague, nephrologist Patrick Rossignol, leads at the French Embassy in Washington, DC. He's doing the same thing as CVCT but on a smaller scale with kidney disease nephrology trials. The other meeting is Critical Care Clinical Trials (CCCT), which is on critical care.
 
We make sure to keep these meetings small enough to foster more interaction. This mindset and type of meeting has grown to become attractive and successful.
 
Thomas: How did CVCT get the attention and attendance of regulatory authorities? Not many conferences I know can draw that broad and deep of an interest amongst regulators.
 
Faiez: That's a great question. It just happened. It’s likely due to the meeting’s high level of credibility from assembling multiple stakeholders and support from various industries. In addition, the meeting is neither promotional nor educational. There is no exhibition. It only discusses science. People from FDA and EMA like the meeting and have found it to be a place where they can speak their minds and hear from others. We have been careful to keep these free minds flowing and interacting at the highest level possible. Needless to say, it happened very slowly. It’s been a tedious, long-term achievement.
 
Thomas: When did you bring the conference from France to Washington, DC?
 
Faiez: That was six years ago, for the 10th or 11th CVCT, upon request by FDA. Only one or two people could travel to Paris due to paperwork authorization and financial issues, but they liked the meeting and said they could be more involved if the meeting was in Washington, DC.
 
Having more of the NIH’s participation was also instrumental. Actually, after each American College of Cardiology (ACC) meeting in March, I spend two or three days with FDA and the NIH to discuss the CVCT program. As you can see, the CVCT program is truly fabricated with all these stakeholders in mind and captures what is interesting to them all.
 
Thomas: I’d like to turn the last part of this interview to you personally. You've had an illustrious career, with many awards and publications. What do you still want to do in your professional life?
 
Faiez: Have fun! I am at the point of my career where I don't need to keep improving it, and I’m not after having big money. I want to have fun with the young fellows and young investigators. I spent a six-month sabbatical at Harvard Medical School, where I met great fellows who are really eager to learn. 
 
I also love connecting people of different backgrounds, which is the philosophy of CVCT. This is the driving force that has led me to invest so much of my time into CVCT. There are brilliant people out there, but sometimes they are siloed. Getting them together is an extraordinary learning opportunity. 
 
Thomas: What is one thing most people don’t know about you?
 
Faiez: Being humble, which I learned from trials. In clinical trials, we are very often fazed. We get a brilliant scientific idea, think we are right, and run a trial of 1000 patients, but the trial turns out to be neutral or negative. We even have trials where the fatality rate rose because of the intervention, not the placebo. You learn to be humble and to be careful because, at the end of the day, you are treating patients.
 
Thomas: Thank you very much, Faiez, for giving us your time.
 
Faiez: Thank you, too. You have been helpful in opening our minds in areas like rare disease. Hopefully, we can make it grow. It will also to be fun for me to learn from these people.
 
This interview was edited for length and clarity.

 
For more information, please visit https://www.globalcvctforum.com/cvct

Interviewed by Thomas Seoh, President and CEO of Kinexum
 
 
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Why Photobiomodulation Might be the Answer to the Opioid Crisis (cont.)

 
What is photobiomodulation (PBM), and how does it help solve the opioid crisis?
PBM is something you have seen on Star Trek. 
 
On Star Trek, when somebody was injured, the doctor would aim a low-intensity laser beam at the injury, and the wounds would heal instantly! That is photobiomodulation (PBM). The effects are not as fast as shown on TV, but the idea is the same: light is shone on people, and they get better more quickly. 
 
PBM is a non-thermal light therapy that reduces the underlying causes of pain: trauma, inflammation, degenerative joints, and neuropathies. PBM utilizes low-intensity lasers and LED devices in the red and near-infrared spectrum (600–1000 nm) to stimulate mitochondrial function, which leads to increased ATP production, reduced oxidative stress (which leads to less inflammation), and better tissue regeneration.
 
There are no known side effects, though occasionally there are some mild short-term treatment reactions. It is cleared by FDA, Health Canada, Europe, and Australia for muscle and joint pain, and it is widely used in the US.

 
Photobiomodulation
 
Evidence for PBM
There are over 6,400 published academic papers indicating that PBM, when correctly delivered, reduces musculoskeletal pain (back pain, neck pain, degenerative joint diseases, and tendinopathies), neuropathic pain (shingles, postherpetic neuralgia, trigeminal neuralgia, and diabetic peripheral neuropathies), dental pain (post-tooth extraction, burning mouth syndrome, and other neuropathies), and other postsurgical pain (hip replacement, total knee replacement, and open heart surgery).
 
There are over 700 randomized controlled clinical trials (RCTs) on PBM. Additionally, there are more than 4,000 laboratory studies looking at the mechanism of action and dose-response. It appears in more than 200 systematic reviews. In 2018, 443 papers on PBM were published.
 
PBM was previously known as Low-Level Laser Therapy (LLLT), but now the National Library of Medicine has adopted “photobiomodulation” as the official medical subject heading (MeSH) [2].
 
PBM is a recommended treatment for oral mucositis (a side effect of radiotherapy for cancer) by the National Institute Health and Care Excellence (NICE) in the UK and the Multinational Association for Supportive Care in Cancer (MASCC) [3, 4].
 
The American College of Physicians Guidelines for Noninvasive Treatments for Acute, Subacute & Chronic Low Back Pain includes PBM as a “strong recommendation” [5].
 
The British Journal of Sports Medicine published a systematic review of the effectiveness of conservative and surgical interventions for frozen shoulder and found “strong evidence” for the effectiveness of PBM in the short term [6].
 
The Lancet published a systematic review and meta-analysis of RCTs for neck pain. It concluded that PBM is "non-invasive, painless, and can be easily administered in primary-care settings." It also stated, "The incidence of adverse effects is low and similar to that of placebo, with no reports of serious events, and the results contrasted with those for drug therapies for which the effect ends rapidly when drug use is discontinued" [7].
 
The British Medical Journal (BMJ) published a systematic review and meta-analysis on the efficacy of PBM on pain and disability in knee osteoarthritis, concluding that "the positive effect from PBM seems to last longer than those of widely recommended painkiller drugs. It is important to note that no adverse events were reported by any of the trial authors, and the dropout rate was minor, indicating that PBM is harmless" [8].
 
The British Medical Journal (BMJ) published another systematic review with meta-analysis, this time on the efficacy of PBM for chronic non-specific low back pain. The meta-analysis suggests that PBM, when used by itself or in combination with other modalities, may achieve a useful reduction in pain for up to 3 months in chronic non-specific low back pain with few adverse effects [9].
 
How does PBM work?

Primary effect (absorption)
There is a consensus that cytochrome c oxidase (CcO) in mitochondria is the primary photo-acceptor of PBM light, with a cascade of molecular events following such absorption [10–12]. There are some additional mechanisms, but the CcO pathway explains most of the benefits seen from PBM.
 
Secondary effects (mitochondrial)
Following light absorption by CcO, there is increased oxygen consumption by mitochondria, with a corresponding increase in ATP production, a burst of reactive oxygen species (ROS) and nitric oxide (NO), followed by a reduction in ROS (i.e., superoxide, hydrogen peroxide) [13–15].
 
Tertiary effect (intracellular)
The changes in ROS, reduced oxidative stress (and subsequent increase in ATP followed by more cAMP), resets NF-