Health Tech: Dr. Kenneth Gruber On How Endevica’s Technology Can Make An Important Impact On Our Overall Wellness

An Interview With Dave Philistin

Failures are OK, especially if you can learn from them. What do you learn? What not to do! Collect enough “no go” areas, and the best approach becomes more obvious.

In recent years, Big Tech has gotten a bad rep. But of course many tech & pharma companies are doing important work making monumental positive changes to society, health, and the environment. To highlight these, we started a new interview series about “Technology Making An Important Positive Social Impact”. We are interviewing leaders of companies who are creating or have created a product that is helping to make a positive change in people’s lives or the environment. As a part of this series, I had the pleasure of interviewing Dr. Kenneth Gruber.

Dr. Ken Gruber is the founder, former CEO, and current Chief Scientific Officer of Endevica Bio, a biotech company developing drugs for conditions which lack any true therapy. A graduate of New York University, with Bachelors and Doctorate degrees, he had a long career as a medical school professor and as a Branch Chief at the National Institutes of Health. In 2008, he began the process of founding a biotech company, Tensive Controls, Inc (recently renamed “Endevica Bio”), which first opened for business in June of 2010.

Thank you so much for joining us in this interview series. Before we dive in, our readers would love to learn a bit more about you. Can you tell us a bit about your childhood backstory and how you grew up?

I was born and raised in Brooklyn, New York; a former city that was reluctantly joined with other cities and counties into greater New York. I was definitely a reluctant student well into my undergraduate years at New York University (NYU). However, I did have a strong interest in biology and research, which led to my winning some notice at the New York City High Schools Science Fair. However, a tour of active duty in the U.S. Army produced a remarkable change in my subsequent academic achievement, allowing me to receive a fellowship to pursue my doctorate degree at the medical sciences campus of NYU.

Can you share the most interesting story that happened to you since you began your career?

In the 1980, my research laboratory at Wake Forest University Medical School began a series of experiments looking at unusual biological activities in a class of mammalian compounds (“peptides”) called “melanocortins.” We were doing very basic work at on compounds with no known therapeutic utility. Melanocortins were best known for regulation of skin color changes in response to the environment (in frogs and lizards), including sunlight-induced tanning (in humans). We did some very interesting work on how a part of the melanocortin structure involved in regulating cardiovascular function could overlap with areas of the structure that mediated coloration. More importantly, we showed how to specifically regulate the expression of cardiovascular activities in melanocortins without affecting other activities.

Years later, melanocortins were recognized as mediators of metabolic rate in mammals, with evidence that they played a critical role in regulating body weight in both obesity and disease-induced wasting of body weight. However, a persistent problem in the development of melanocortin drugs was an elevation of blood pressure and heart rate (i.e., cardiovascular activity). Literally scores of melanocortin patents in the U.S. and European Union were rendered useless by this. My colleague, Mike Callahan, and I believed we understood the problem, felt we could devise solutions to the presence of elevated cardiovascular activity, and formed a biotech company to develop melanocortin drugs safe from cardiovascular side-effects.

Our success in producing safe and effective melanocortin drugs formed the basis for a series of U.S. and European Union patents, and the raising of over $8 million of investment from private investors and the National Cancer Institute. The University of Missouri and the FDA have also been notably supportive of our commercialization efforts. All this from a series of basic research studies performed over 35 years ago, that were deemed (by NIH Review Panels) as unfundable at the time. As a reviewer of many grant applications, I’m always reminded to be cautious when I begin to harshly judge an application as investigating topic that I don’t find to be relevant to current research areas.

None of us are able to achieve success without some help along the way. Is there a particular person who you are grateful towards who helped get you to where you are? Can you share a story about that?

When I was a rising freshman in college, I had a biology instructor named Richard (Dick) Libbin. We became quite friendly during the course, and Dick inquired if I was interested in doing research during the summer. In addition to teaching biology, Dick was working as a Research Scientist at NYU, and thought he could get a summer job for me. This summer position, with Dr. Gilbert Stanton in Biochemistry, led to multiple summers of research experience with him, a part-time position as a research technician during the school year with Dr. Howard Grob in Physiology, and eventually admission to the Graduate School Department of Basic Medical Sciences and a Teaching Fellowship. The contacts I made at NYU included Dr. Milton Levy (Chairman of Biochemistry), who wrote me a letter of recommendation to his former student, Dr. Sidney Udenfriend, then Director of the Roche Institute of Molecular Biology. Dr. Levy’s letter was instrumental in my being offered a post-doctoral fellowship at Roche Institute (in Dr. Udenfriend’s research group), which helped set me on the path to where I am today. And all because of Dick Libbin’s offer (to an 18-year-old freshman Biology student) to help me get a summer undergraduate research position.

Can you please give us your favorite “Life Lesson Quote”? Can you share how that was relevant to you in your life?

Never be afraid of trying. If you don’t try, how can you succeed?

When I was a graduate teaching fellow at NYU, I was talking to a professor (Dr. Eli Goldsmith) after we proctored an examination together. We were discussing what I was going to do after my upcoming graduation. I mentioned that I was interested in a post-doctoral fellowship program at a very prestigious institute of molecular biology, but I didn’t think I was going to be very competitive. Dr. Goldsmith replied that there was a way of guaranteeing that I wouldn’t get the fellowship, which was by simply not applying! I applied and received an offer from the Director of the Roche Institute of Molecular Biology to join his laboratory. That good advice, and my subsequent fellowship training, set me on the career path that I’m still on today.

You are a successful business leader. Which three character traits do you think were most instrumental to your success? Can you please share a story or example for each?

A critical characteristic of many successful people is the ability for “delayed gratification.” Every high school graduate that made a decision to go into some form of higher education or training rather than look for a job in order to purchase a new car, has made a decision for delayed gratification. Often a decision with an immediately beneficial effect has poorer long-term prospects than a decision with less immediate, but decidedly greater opportunities in the future.

I had a unique instance to practice the “delayed” concept when I was finishing my doctorate, and looking for a post graduate position. I had several faculty search committees that were very interested in me, including the University of Hawaii (!). However, much to the surprise of one of the young professors in my department, I decided to accept a post-doctoral fellowship at a very prestigious institute of molecular biology, joining the institute director’s research group. That decision, and the research training (and publications) ensuing from it, supercharged my future career advancement.

Ok super. Let’s now shift to the main part of our discussion about the tech tools that you are helping to create that can make a positive impact on our wellness. To begin, which particular problems are you aiming to solve?

Many diseases share the development of a common condition of lean body mass (all organs except fat) wasting termed “cachexia.. While first described by Hippocrates in the 3rd century B.C., the basis for cachexia remained elusive. Examples of these disease that produce cachexia include: cancer, infectious diseases, renal failure, among many others. It’s now appreciated that activation of the immune system produces deleterious effects in both peripheral organs and the brain, which contributes to lean body mass wasting. Many of the symptoms of cachexia are similar to starvation. However, in cachexia the loss of lean body mass is disproportionate to food intake; cachexia produces an inefficiency in the utilization of ingested calories. An example of the medical importance of cachexia is the evidence that up to 40% of cancer deaths are directly due to cachexia, rather than the underlying malignancy. Other diseases that produce cachexia have incidences of 20–40%. There are no effective treatments for cachexia; thus it is a life-limiting condition, resulting in a person dying within weeks, months or even several years.

How do you think your technology can address this?

Fairly conclusive experimental and clinical evidence supports the hypothesis that hyperactivity of the brain melanocortin system produces a hypermetabolic state, which is a critical feature of the cachexia syndrome, and that drugs which are antagonists of the brain melanocortin system will reverse many of the hallmarks of cachexia by lowering metabolic rate. Our drug is a melanocortin receptor antagonist, and (unlike other melanocortin antagonists) can be administered parenterally to reverse cachexia. This underscores the problem in the development of anti-cachexia drugs; the target metabolism regulating melanocortin receptors are behind the blood-brain barrier (BBB). Our drug was designed to cross the BBB in order to exert anti-cachexia effects. This therapeutic effect has been demonstrated in five rodent models of cachexia (typically one or two rodent models are used to support drug development) and in a multicenter veterinary hospitals trial of our drug in client-owned dogs with cachexia (an almost unheard of demonstration of efficacy in a drug that is destined for human development). Why is the latter so important? Because less than 30% of successful therapeutic efficacy experiments in rodents translate into efficacy in humans. However, efficacy in dogs has a greater than 85–90% translational efficacy to humans; three times than of rodents!

Can you tell us the backstory about what inspired you to originally feel passionate about this cause?

Cachexia was first described and named by Hippocrates in the 3rd century B.C. Since then and until relatively recently, the precipitating cause of cachexia (high levels of proinflammatory cytokines from the immune system) was not known. I became interested in developing in melanocortin analogs in the 1980s, when everyone thought that melanocortins were irrelevant to human health. I went on to a career in research administration, but eventually came back to melanocortin research.

I started with an idea (in retrospect quite naive) that I could make peptides (a class of compounds found in living organisms) drug-like (peptides are not very stable, the antithesis of a drug); melanocortins are peptides! However, I struggled in deciding which of the diseases that had potential melanocortin involvement would be my drug development target. I decided on cachexia. Despite being called (in writing) “naive” by an NIH Review Panel, when I described my efforts to produce peptide drugs that would cross the BBB, I persisted in continuing my research. I don’t want to give up on this mission because I truly believe a solution to cachexia could change the world.

How do you think this might change the world?

There are many diseases/specific types of cancer with a high incidence of cachexia. No one knows what the natural history of those conditions would be in the absence of cachexia, or how this might enhance the efficacy of treatments. For example, in many forms of cancer, the degree of cachexia is inversely related to the efficacy of the cancer treatment.

Evaluating the efficacy of new cancer therapies in clinical trials is a particularly important setting for co-use of an anti-cachexia drug. As noted above, up to 40% of cancer patients die from cachexia, rather than the underlying cancer. However, in cancer drug clinical trial, the death of a patient on drug is a failure of the drug, even if the death was really produced by cachexia. So the question is, what would happen in cancer clinical trials if there was no cachexia? I suspect that if we can solve for cachexia in cancer, then we would see many more people survive the disease without compromising their quality of life.

Finally, children with renal failure or cancer often have cachexia. Indeed, with cancer, both the disease as well as the anticancer treatment can produce cachexia. This presents a conundrum because (as noted above) cachexia produced a relative state of starvation, and this state can coincide with growth spurts in children, resulting in a failure to achieve their predicted adult height. This can have life-long consequences, even if the child is cured of the cancer (over 80% of pediatric cancer patients have greater than a 5 year survival rate) or kidney disease (e.g., kidney transplantation). Stunted growth significantly below the adult average height is a risk factor for poor cognition and educational performance, low adult wages, and lost life-long productivity. Attempts to calorie load these children have failed, essentially making their health problems even worse by inducing obesity, without any amelioration of the inhibited growth.

Keeping “Black Mirror” and the “Law of Unintended Consequences” in mind, can you see any potential drawbacks about this technology that people should think more deeply about?

I get the impression that many people believe that control of metabolism is like adjusting a light with a dimmer; you can turn it up or down as you need to; i.e. lose weight or gain weight as needed. Its not quite that simple. Many actions of the brain that control peripheral activities — e.g. blood pressure, heart rate, metabolic rate — operate around set points for optimal regulation. Repeatedly disturbing these activities, either by drugs or environmental stress can change a set point; sometimes temporarily, just as often permanently; producing the need for life-long drug therapy.

Melanocortins are powerful regulators of metabolism, and should only be taken as prescribed.

Here is the main question for our discussion. Based on your experience and success, can you please share “Five things you need to know to successfully create technology that can make a positive social impact”? (Please share a story or an example, for each.)

1. Pick out an objectively big problem that needs a solution, and one very dependent on background preparation (a great reason for delayed gratification to get more education/training) and your success, without other conditions being required. Such problems provide “room” for many successes, some of which you might not have even thought of. A perfect example is when I decided, as someone with a background in melanocortins and their cardiovascular effects, to explore drug development in cachexia rather than obesity.
   Melanocortins have been implicated as a causal factor in both conditions. However, obesity is a multifactorial condition, dependent on more than just appetite and metabolic rate; i.e. too many other variables. Cachexia was a much more straight-forward problem, it was becoming obvious that melanocortins had the potential to be potent anti-cachexic agents, if only they could be made more drug-like; especially the ability to cross the blood-brain barrier (BBB). This provided me with a huge medical opportunity, with well defined goals that had to be achieved, and importantly a clinical population that would be very adherent; e.g., no multifactorial psychological reasons producing a failure to eat.
2. Failures are OK, especially if you can learn from them. What do you learn? What not to do! Collect enough “no go” areas, and the best approach becomes more obvious.
3. Serendipity (luck) in professional endeavors is something often can be made by hard work toward a goal, and paying attention to emerging opportunities. My work on anti-cachexia drug development provides an example. We needed to make a peptide drug that would cross the BBB; an objectively difficult task. However, we noted that there reports in the literature of peptides which, for unknown reasons, could cross the BBB. We collected these reports and made what is called a “chemical library”; a collection of structures that have a common biological or chemical activity. We compared the structures of these BBB-penetrating peptides and came up with a sequential series of composite structures, assessed them in appropriate assays, and produced our final drug candidate in about 18 months of work. Many people attributed our success to luck. Why is going to a library and studying to come up with a solution to a problem “luck”? People have essentially been doing this since early Greek and Roman times.

If you could tell other young people one thing about why they should consider making a positive impact on our environment or society, like you, what would you tell them?

I divide the potential long-term impact of a person on our “world” (human society and/or the environment) into three categories. Relatively neutral, relatively positive, or relatively negative. Most of the population falls into the first (“neutral”) category, for many reasons, including financial. However, there are an unusually large number of people who seem to enjoy behavior that that is objectively negative to society and/or the environment. That behavior is often for financial/professional reasons, but sometimes its just because… This means that those of us who try to do things that are beneficial for society should try to do these things for as long as possible in our lives. I’ll provide an example.

My father retired in his mid-50s, and spent the rest of his life in retirement (30 years). That sounded like a pretty good life to me, and that was my plan until that time actually came. Then I realized that just because I had the financial security to retire and just “play,” was that what I really wanted to do? How did I want people to remember me? As a guy who just played for a few decades? I decided to do what I always thought I could do (and even did in my early career); design drug-like peptides to cure pathological conditions with no good treatments. Starting a biotech company was just a means to that.

Is there a person in the world, or in the US with whom you would like to have a private breakfast or lunch, and why? He or she might just see this, especially if we tag them. :-)

Michael Gerson, the political columnist. Based on his columns, one of the most decent people writing political commentary, even though I disagree with him on several social/medical issues.

How can our readers further follow your work online?

Our website, EndevicaBio.com, is a good place to start and you can sign up for our email list there. One could also do a simple Web search with an engine like Google to quickly find press releases and articles about us.

Thank you so much for joining us. This was very inspirational, and we wish you continued success in your important work.