Summer 6-2017 Newsletter

Summer 6-2017 Newsletter


Newsletter – Summer 6-2017



By: Alexander Fleming, M.D.,

Founder and Executive Chairman

We have just marked a major milestone for Kinexum by bringing on Thomas Seoh to lead the company as its CEO.  We are very fortunate to have someone at the helm as talented and distinguished as Thomas. He will ensure that Kinexum serves its clients and its missions increasing well for years to come.  Thomas brings a 25+ years career as a highly successful life science executive and entrepreneur in senior leadership positions of public and private pharmaceutical, biotech and medical device companies.  His multifaceted experience and his undergraduate degree in philosophy and history and law degree from Harvard University reflect a voracious appetite for understanding the world of healthcare and developing products to support it.  (read more)




By: Elizabeth Whalley Buono, BSN, RN, MBA, JD

I recently was asked to take part in a series of expert workshops supporting FDA’s efforts to reduce the growing epidemic of opioid abuse, dependence and overdose in the United States. The first workshop, focused on packaging innovations, sought to gather input from a multi-disciplinary team to identify key intervention points; examine data needs and guiding design principles for the development of packaging, storage and disposal solutions; and contemplate the intricacies of integrating such solutions into the current healthcare marketplace. With representatives from academia, manufacturing, patient and provider groups, payor organizations, and government – the conversation was rich yet circular. What became clear to me throughout the day was that this issue, with its layers upon layers of complexity, truly was the perfect storm of public health crises. (read more)


By Lawrence Steinman, MD

Guest author Dr. Lawrence Steinman is Professor of Neurology, Neurological Sciences and Pediatrics at Stanford University and served as Chair of the Stanford Program in Immunology from 2001 to 2011.

We all know the names Banting and Best.  Nearly one century ago in 1923 Frederick Banting and his department chair, John McLeod won the Nobel for the discovery of insulin. Link to reference  Banting shared his prize money with his younger collaborator, Charles Best, who was a medical student at the time.   The saga of Banting, Best and McLeod and the discovery of insulin is legendary.  Yet type 1 diabetes, remains a relatively neglected disease compared to its counterpart, “the other” diabetes known as type 2 diabetes.  At the recent ADA meeting the paucity of presentations aimed at developing disease modifying therapies for type 1 diabetes was glaring.  I refer to the attention given to Type 2 diabetes in comparison to that devoted to Type 1 diabetes as “Two Minus One”. (read more)




By Simon Bruce, MD

I joined Bristol-Myers Squibb (BMS) in 2000 right out of fellowship at the NIH. At that time, Dr. Leon Rosenberg, ex-Chief of Medicine at Yale, who had just stepped down as Chief Scientific Officer BMS, was warning about the dearth of physician-scientist support and a new organization for Patient-Oriented Research was forming to try to extend or rekindle an important lineage of bench-to-bedside research. Managed care was leading to profound changes in academic medical centers from where such contributions had historically arisen.  As a yeoman drug developer, primarily working in Phase2/3/4 clinical trials, I have had good fortune to be closely associated with both drug discovery and early clinical development teams. I learned that, in industry, early clinical development consisted mainly of template protocols for Single Ascending and Multiple Ascending (SAD and MAD), first-in-human studies, conducted by clinical pharmacologists and kineticists who managed the Clinical Pharmacology department (Clin Pharm). (read more)


A unique and important meeting, The World Congress on Targeting Metabesity (Metabesity2017), will take place 30-31 October 2017 in London, UK.

The term Metabesity expresses the idea, for which scientific evidence has been accumulating over recent decades, that major non-communicable diseases of aging (such as diabetes, cardiovascular diseases, neurodegenerative diseases and cancer) may have common metabolic roots, and thus may be susceptible to common solutions.  

Metabesity2017 aims to serve as a call to action and generate a roadmap for a tractable “moonshot” program to extend healthy aging by targeting these major illnesses of old age. 

The congress will assemble world-renown scientists with their peers in policy, industry, government and other disciplines to map a way forward that will involve innovative, large-scale coordination between the public and private sectors, and will have other major medical, policy and ethical ramifications.

The co-chairs of the congress are Lawrence Steinman, M.D., George A. Zimmermann Professor of Pediatrics, Neurology and Neurological Sciences at Stanford University, and G. Alexander Fleming, M.D., Founder and Executive Chairman of Kinexum, and a former senior FDA reviewer.

Confirmed speakers to date include scientists who are members of the Boards of Roche and of the Novo Nordisk Foundation, as well as the Chair of the Nobel Assembly that selects the recipients of the Nobel Prize in Medicine or Physiology.

Other speakers that have been invited include senior officials of health authorities in the US and UK

The hope of the co-chairs is that Metabesity could become a ‘Davos-like’ annual gathering that will build upon the call to action and roadmap to actual implementation of scientific knowledge through public and private policies to help people live longer, healthier lives.  The conference website is



Attend with your team!  One free registration for four paying delegates.  Please contact the 2017 Metabesity Registration Department at This email address is being protected from spambots. You need JavaScript enabled to view it. for more information.

Click on the LINK below to open the online registration form.

Online Registration


We introduce you to the newest members of the Kinexum team:


Gabrielle Wiederkehr, MSc

Regulatory Affairs and Project Management

To learn more about Gabrielle

Theo Gana, MD, Ph. D

Clinical Development



To learn more about Theo


Asoke Mukeherjee, Ph. D

Regulatory Affairs and Pre- Clinical

To learn more about Asoke


Kinexum designs, guides and manages strategic and operational solutions to the regulatory, manufacturing, nonclinical and clinical development, as we II as, commercial challenges necessary to bring healthcare products from proof of concept to commercialization.

Our experts, whether as individual consultants or as integrated teams, have helped over 300 large and small organizations across the world to reach high value milestones expeditiously and efficiently.

Kinexum specializes in crafting creative but sound and integrated solutions across scientific disciplines, therapeutic areas, product modalities and business stages.

We would be pleased to assist your organization, please contact us at info@ or visit our website for more information.

Contact us:

Kinexum Services LLC

PO Box 1260

550 East Ridge Street

Harpers Ferry, WV 25425

P - 304-535-3037

F - 304-535-3166

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A Milestone for Kinexum continued …

Thomas is among the most incisive thinkers and strategists whom I have ever known.  He will contribute enormous value both to our clients as an advisor and to Kinexum in leading its daily quest to be a high performing, learning and teaching organization.

It is so gratifying to have seen Kinexum become an acclaimed resource for supporting the strategic, technical, and operational needs of small and large life science companies.  From its original expertise in the development of small molecules for metabolic diseases, the firm has expanded its capabilities across multiple therapeutic areas to deliver high-value solutions for over 300 companies across the globe.  Kinexum has expertise in the domains of small molecules, biologics, diagnostics and medical devices, nutritional products, and data systems across the fields of diabetes, metabolic disorders, healthy lifespan agents, cardiovascular diseases, oncology, gastroenterology and others. 

However, all the above services are available from individuals and companies across the world, and we often collaborate with many of them.  We increasingly recommend other companies to prospective clients because we want to focus on what we do best—provide high value strategic guidance integrated with core communication services (regulatory submissions and technical, business, and financing documentation).  Yes, we will continue to provide technical writing and submission services, and clinical and manufacturing site inspections but only as part of a more comprehensive program. 

From a personal standpoint, I am overjoyed by Kinexum reaching this milestone and taking on an outstanding leader. Thomas at the helm will allow me to spend more time with our project teams.  I will have more time to advocate process innovation in the translation of life science products from research through development to regulatory evaluation to commercialization.  Kinexum will increase even further its pro bono support of consensus statements and publications, which started in 2001 with its major role in the ADA publication* on endpoints for type 1 diabetes trials. Very simply this paper enabled the development of treatments for T1D.  Kinexers have since made many important contributions to the fields of health product development—and much more is to come.

Thomas and I first met at the Leigh Thompson Renaissance Conferences in Charleston, which Kinexum organized in 2004 and 2005.  This highly successful conference brought together a wide variety of stakeholders to support innovation in addressing major healthcare challenges.  Kinexum is taking on an even more ambitious task in co-organizing the inaugural World Congress on Targeting Metabesity in London, October 30-31, 2017,   Connecting people and ideas is the essence of what Kinexum does—and will do even more.

To your health and that of people across the globe,


* C-Peptide Is the Appropriate Outcome Measure for Type 1 Diabetes Clinical Trials to Preserve β-Cell Function. Report of an ADA Workshop, 21–22 October 2001

Jerry P Palmer, G. Alexander Fleming, Carla J. Greenbaum, Kevan C. Herold, Lisa D. Jansa, et al.

The Opioid Epidemic: A Perfect Storm continued …

Unraveling the problem will require a thorough understanding of the intricacies of human behavior – especially those related to addiction. Starting with the patient who fills the prescription, unintentional non-adherence, driven by forgetfulness, health illiteracy or simple misunderstanding, makes this problem in certain limited ways no different than the general “medication adherence crisis” that has been recognized and studied. Non-adherence has been proven to cost the US healthcare system hundreds of billions of dollars annually and to lead to immeasurable and preventable negative health outcomes. For the last decade, we’ve been trying to figure the whole “why don’t people take their medication as directed” problem out – and to address it - to no avail. What we’ve learned is that the reasons people don’t take their medications correctly are as individual as the people themselves and thus, so are the solutions.

To this conundrum, we now add on the problems associated with the nature of these particular drugs themselves.  Opioids further confound the problem of non-adherence (which we have not been able to solve) in unbounded ways. Opioid’s psychoactive effects and the propensity for dependence development converts unintentional non-adherence to intentional non-adherence (although one could argue about the meaning of intentional activity in addictive behavior).  What I mean to say is that we are no longer dealing with patients forgetting or failing to understand – but rather - seeking. Intentional activity is a whole new ball game and one for which virtually none of the innovations designed to address forgetfulness and literacy will help. Combine that with provider prescribing practices and rules around pharmacy and hospital reimbursement, and you’ve added fuel to the fire. Whether on the part of the patient or a third party (through diversion or sharing), intentional non-adherence draws into the conversation topics associated with access limitation, SUD diagnosis and treatment, traceability, and criminality, among others. Furthermore, the problem has created cultural issues of stigma and shame which force open discussion and self needs identification underground.

-          And then there’s the money. Both legally and illegally, it’s a profitable industry - and I’ll leave it at that for purposes of this discussion.

-          And what about patients living in chronic pain? It was obvious in the room that the concept of limiting access struck fear in the hearts of those advocating for the rights of those living in chronic pain.

-          And what about our love of privacy? We Americans delude ourselves into thinking that we have some - and we are recalcitrant in giving any up - regardless of whether actual or perceived.

-          And what about the gateway issues? If limiting access to opioids will drive current misusers to illicit drugs – how does that help?

For every proposed solution, another convoluted problem rose its ugly head. At the end of the day, only a precious few bright lines were left on the drawing board.  First, the criticality of having all stakeholders engaged, connected and aligned in the development and deployment of potential solutions was obvious. Second, given the mind-blowing statistics around the speed and the pervasiveness of the epidemic we’d better get used to the fact that our current rules of play need to be off the table and we’d better get moving.  In the war against the opioid epidemic, perhaps Patton would be right in opining that a good plan violently executed right now is far better than a perfect plan executed next week.

Two Minus One continued

Type 1 diabetes deserves far greater attention.  We know that the disease is inflammatory, and probably autoimmune.  We know the identity of the targets of the immune attack-islet antigens including proinsulin, glutamic acid decarboxylase (GAD), zinc transporter, and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP).  We know that in childhood diabetes the development of a high affinity antibody to proinsulin is the harbinger of the development of clinical disease.  The immune attack is highly localized with general sparing of the exocrine pancreas, and pinpoint destruction of the islets of Langerhans.

Despite this wealth of knowledge gained over the past century since Banting and Best (and McLeod), there have only been a few attempts to tolerize the immune system, so that a “cease fire” could be induced to silence the immune destruction of the insulin-producing islets.  At the recent ADA meeting that concluded two weeks ago in San Diego, the following trials in type 1 diabetes were reported:

Tolerizing to GAD

Results of a five year study to prevent the onset of type 1 diabetes, by tolerizing the immune system to GAD were presented in a session entitled “Double-blind, Randomized Investigator-initiated Study to Determine the Safety and the Effect of Diamyd® on the Progression to Type 1 Diabetes in Children With Multiple Islet Cell Autoantibodies."  Children at risk for type 1 diabetes who already had GAD antibodies and an antibody to at least one other islet antigen were given two doses of 20 micrograms of GAD in Alum or placebo at entry and 30 days later, a classic prime and boost regimen.   There was no significant effect on preventing type 1 diabetes in the children enrolled in this small trial of 50 individuals.  From my perspective as an immunologist, I have wondered over the years why alum-the only approved adjuvant for vaccines used here in the US, would be added to GAD in an attempt to tolerize.  In many common vaccines ranging from tetanus immunization to HPV immunization, alum is a key component. Alum is added to accomplish the opposite of tolerization, namely vaccination! Fortunately the trial with alum mixed with GAD was safe, and no untoward responses to GAD were reported. Link to reference

Oral Insulin

In a randomized placebo controlled trial of individuals with a relative with type 1 diabetes, who themselves had two or more antibodies directed to beta cell targets, daily administration of 7.5 mg of insulin failed to prevent disease in a study that followed patients for 8 years.  The strategy here was to give insulin orally in an attempt to tolerize the immune system against autoimmune responses to insulin itself.  Unfortunately this was yet another setback in attempts to tolerize the immune system by giving antigen, in this case insulin, via the oral route. Link to reference


Gleevec is a magic bullet in cancers where the Bcr-Abl tyrosine kinase is mutated and “locked” in an “on-state”.  It is approved for chronic myelogenous leukemia, acute lymphoblastic leukemia and certain gastrointestinal stromal tumors.  Gleevec and other tyrosine kinase inhibitors show some benefits in pre-clinical models of autoimmune disease.  An early stage safety trial was done in 67 patients with type 1 diabetes.  Insulin requirements were described as reduced by nineteen percent.  Principal investigator Dr. Stephen Gitelman said, “The conservative estimate is that beta cell function was maybe 19 percent better at one year. So it’s not a slam-dunk home run.”  Slam-dunks and home runs are not often in the same sentence, as they represent metaphors from two sports-basketball and baseball.  Repurposing a cancer drug in an autoimmune disease is like applying a basketball metaphor to the “national pastime”. Link to reference


The previously published study of alefacept was featured at the ADA session on Therapies to Preserve Beta Cells in Type 1 Diabetes as an example of a therapy that demonstrated efficacy on the primary endpoint of C-peptide by 24 months. Link to reference The authors had described the 24-month results of the T1DAL trial as providing “the most promising proof of concept to date that a brief course of a targeted, well-tolerated immune intervention in the new-onset period can produce lasting clinical and metabolic benefits, long after cessation of therapy.”  The authors also acknowledged that a similar magnitude of C-peptide preservation was also observed after longer-term follow-up in patients treated with anti-CD3 monoclonal antibodies (teplizumab and otelixizumab), but contrasted the greater safety of alefacept with these agents. Like Gleevec, however, alefacept’s blunt mechanism of action to deplete T cell still causes safety concerns.  It is encouraging to see studies that demonstrate efficacy against T1D autoimmunity, but it is time to limit such trials to agents that start with appropriate safety profiles for the condition being treated or prevented.

Metformin REMOVAL Trial

On the other hand, a JDRF-supported study reported at ADA reflected a large effort to show an effect that the intervention was unlikely to deliver. Metformin was tested in a trial in adult type 1 diabetics. Cardiovascular risk was the primary endpoint with the readout as significant reduction in mean far-wall carotid artery intima-medial thickness (cIMT) at 3 years.  The role of metformin in reducing CV risk in type 2 diabetic patients has been controversial since favorable findings were observed in the non-randomized metformin treatment arm of the UKPDS. Link to reference The double-blind placebo controlled REMOVAL Trial of 1000 mg twice daily or placebo as adjuncts to insulin failed to meet the primary endpoint. Link to reference Curiously, the report in LANCET Endocrinology and Metabolism cited a tertiary efficacy result to justify the second part of the conclusion: “These data do not support use of metformin to improve glycaemic control in adults with long-standing type 1 diabetes as suggested by current guidelines, but suggest that it might have a wider role in cardiovascular risk to reference  It is unclear what wider role the authors could be referring to. The Removal Trial raises the question: Does JDRF simply not have enough diseases modifying or preventing approaches to support, or is it being distracted from its mission to cure type 1 diabetes?

Going Forward

The trials reported at the ADA for type 1 diabetes were few, and results were in general not encouraging at all.  Type 1 diabetes, that immune disease where the beta cell is quite specifically targeted, remains an unsolved problem. The targets of the immune system in type 1 diabetes are quite well-known.  Several new approaches to specifically tolerizing the immune system to stop the destruction of islets have been designed and some are being taken forward into the clinic. Link to reference 

In the next few years we hope to see successful clinical trials in type 1 diabetes, by which the major pathophysiologic defect-antigen specific autoimmunity-is addressed.  Anthony Cerami, the discoverer of the A1c hemoglobin assay, has written a poignant article about what we can learn from failures in translational medicine: “The hurtful feelings associated with failing can be devastating especially if the failure occurs after the investment of a considerable effort. The reflection of a lifetime of work in translational medicine has revealed that the study of failures can give birth to new insights that can be explored with important consequences.” From Cerami A, The value of failure.  Link to reference

Diabetes congresses that are “Two Minus One” affairs these days, might in the future feature bold investigators who might report success. In type 1 diabetes the last decisive advance, the discovery of insulin, is nearly 100 years old.  Perhaps trials aimed at precise tolerization of the immune response to targets in the beta cells will produce those elusive stories, and at last we would have a disease modifying therapy for type 1 diabetes.

Conflict of Interest: Steinman is a co-founder and Executive Chairman of Tolerion

Challenges of Early Clinical Development Continued …

These studies were referred to ungraciously as “feed’em and bleed ‘em” and focused on ensuring acute safety and tolerability but provided little insight into possible early efficacy. Management prioritized a goal to better leverage emerging biomarkers to get more clinical value out of the SAD and MAD trials and better inform Cost/Risk/benefit calculus and Go-No-Go decisions in the context of overall “portfolio management”. To this end one of the first initiatives was to hire more physicians into the Clin Pharm group.

On its face this structural change made sense, although it encountered challenges. Firstly, there was not a natural fit between the new physicians, most of whom were transitioning to industry from practice and did not have specific training in human research, with the entrenched guard of PK scientists who still managed the departments. This also created a vacuum whereby “late development” representatives, like me, had a renewed interest in what clin pharm was doing and the size and budgetary heft to potentially stick our noses into things we weren’t entirely expert at. One specific example sticks with me;  our Vice-President of late development dismissed the idea of including an OGTT in an early study of a new DPP4-inhibitor because it “was a diagnostic test that lacked clinical relevancy”. I was confounded to see the clin pharm group accept this without comment. I was too new to raise a fuss but consoled myself that an additional “food effect” study component would be good enough to look for the expected increase in post-prandial incretin hormones that could confirm the mechanism of action. I didn’t understand at the time that a “food effect” study involves drug administration within 20 minutes AFTER a meal is consumed, too late for a DPP4-inhibitor to work, far less be able to discern small potential differences between doses.  That was a big fail that required much work to get keep the program on track.  Mostly because, in the  group’s mind, a negative finding in an underpowered or otherwise confounded study design still means that “the drug don’t work”, despite that this is a fundamental and remedial logical fallacy.

The next management intervention was to empower clin pharm further by changing the name to “Translational Medicine” and hiring new leaders with true academic research bone fides. MD-PhD leaders did empower the early development groups.  So much so in fact that at two different companies, separated by almost 10 years, I was unable to convince translational medicine to consider a stepped hyperglycemic clamp study to clarify how plasma glucose concentrations might be impacting the dose-response curves for new SGLT2-inhibitors. Clearly part of the fault lay in my inability to finesse the idea but at the time it did seem that some of the resistance reflected the new empowered perspective that translational medicine professionals were the only people qualified to conceive of and execute such studies. In fact we were told to stand down and let clin pharm takeover another project to conduct a hyperlactate clamp for a novel gluconeogenesis inhibitor even though the reason it needed to be done was because clin pharm had designed and executed a study in combination with metformin that caused 2 cases of lactic acidosis. Noone was irrevocably hurt and I had the opportunity to talk directly with the medical reviewer at FDA because the entire clin pharm group happened to be unavailable the day he  called to put us on medical hold. We avoided this by doing an outpatient proof-of-concept study with intensive proactive safety monitoring. The drug was shown to work but not as well as metformin but I took the opportunity to move on prior to the readout.

It is normal in any organization for departments to have “turf” issues but to this day I think about my own inability to get more traction on the SGLT2 issue, not due to any personal need to be right, but because it probably was relevant at the time. For example, no one knew to what extent the dose-response to SGLT2 inhibitors was modified by the ambient glucose level. Moreover it was apparent early on that the simple explanation of “lowering the glucose excretion threshold” to allow glucosuria was indeed too simple, since the early studies were inducing glucosuria in normal subjects. Assuming that glucose and SGLT2i compete in some way for renal tubule reuptake sites, how would we know if you needed a different dose when you were hyperglycemic but maybe a lower dose when you were normoglycemic.  At the time of launch there was no data on whether a too large chronic dose at near normal glycemia might affect counter-regulation such as gluconeogenesis to defend fasting glucose levels. Such studies are now being done by academic researchers and have relevance to SGLT2 side effect profiles.

One further management innovation was to task translational medicine with responsibility up through POC (proof-of-concept) for new agents.  The idea was that by focusing on a true Go-No-Go milestone this would draw translational medicine into alignment with the overall drug development enterprise, which admittedly is daunting in its complexity and multiplicity of relevant perspectives. This incentive was misguided because early clinical development does not have the budget or the staff to execute multi-center trials and in diabetes real POC requires at least 1-3 months with a minimum of 30 subjects/group often across more than one experimental dose, to establish meaningful reduction on A1C, the clinical and pivotal registrational endpoint. Thus the business pressure to deliver a certain number of POCs per year (and hence receive bonuses) may have incentivized even the most well-meaning colleagues to focus more on studies that were achievable as opposed to optimally instructional to the program. I had what I consider a privilege to be the late development liaison to all early metabolic teams at Novartis and found that the task of supporting them through influence rather than position power was doable but difficult to institutionalize. Novartis also tried a  strategy of promoting the heads of translational medicines to become the chiefs of all clinical development, which might have been a good way to infuse a deeper clinical-research ethos throughout all stages of development. Unfortunately the early results were hampered by the complaint from savvy late development staff that they were being lectured to by the new leaders.  Novartis rapidly cycled through a few such experiments.

It is probably fair to say still that the voice and impact of the ethos of the “physician-scientist” is not fully leveraged in early drug development in any institutionalized way.  For one thing, there simply aren’t that many physicians or scientists with a formal background in human clinical research and link to the lineage of the heyday of US clinical academic medicine before the age of managed care and medicine by algorithm. From a business perspective companies will continue to hesitate to even think about early mechanistic studies out of a sense of risk of the unknown. There are differences between large and small companies as well; In large companies it can be argued that the value of a risky but meaningful study is that it can substantively inform Go-No-Go decision making, i.e. a well-designed study that yields negative results can be valuable. In contrast, for a small company, a poorly designed study that appears to yield positive results may be crucial for partnering.

While small companies may only think short-term, large companies all have onerous hundred-page documents with copious flow-charts mapping out all stages of drug development, but at the practical level the teams often feel stymied and the integrated development plans often seem to be pulled out by project managers rather than arising organically from the best efforts of the different departments. My experience going from large pharma to small biotech and back is that there is much untapped engagement within development teams. Even though there are so many players, most of whom do not have specific healthcare training, there is an abundance of goodwill in terms of wanting to contribute meaningfully to important new medicines. There is also a general reluctance to exercise judgment, partly due to the hierarchical nature of business but also because there isn’t any definitive textbook and more of a tendency for participants to overweight their most recent experiences rather than extract general heuristics. In an industry where so many projects are expected to fail, people don’t always discriminate good plans from bad plans because they have no way of gauging why they succeeded or failed. Obviously that is a key reason people reach out to Kinexum, looking for a reliable authority.  Clearly this is an exciting aspect of drug development where no one has cornered the market.