This week, we’re taking a break from our regularly featured section on avoiding medication mistakes to bring you this exclusive interview series with NuSirt CEO, JC, in which he talks about some of the groundbreaking work his company is doing to increase the effectiveness of metformin.
Steve Freed, Publisher, Diabetes in Control: How did you come to be involved with NuSirt?
Joe Cook, Jr: I’ve been in the space of developing medicines since 1965. I joined Eli Lilly and Company after graduating from the University of Tennessee.
During my career at Lilly, I was responsible for operations, manufacturing and technology. Along the way, I became involved in the development of the first recombinant insulin, particularly in the manufacturing of it. I saw how precious the production of insulin was to patients. On special occasions, we shut the factory down for half a day and had kids come in from a diabetes camp in central Indiana. Their visits made such an impact on the men and women who ran the production facility and me. I became attached to diabetes. I do not have diabetes and no one in my immediate family has diabetes. However, my grandfather did die from complications associated with diabetes.
I was able to retire early from Lilly at the age of 51 in 1993. At the time of my departure, I was Group Vice-President of Worldwide Operations responsible for all manufacturing and technology. For the next 10 years, from 1993 to 2003, I became involved in biotech, working for a diverse number of companies, one of which was Amylin Pharmaceuticals. In 1998, the Amylin board asked me to become chairman and CEO of the company. For five and a half years, I was CEO of Amylin. I turned over the CEO reins in 2003 and continued as chairman until 2009. At Amylin, I was deeply immersed in diabetes as we were trying to figure out how to develop both pramlintide, which has the brand name Symlin, and also explore the GLP-1 space. At the time, Dr. Daniel Drucker was making quite a strong statement about the scientific validity of GLP-1 as a potential area for concentration and developing new medicines for people with diabetes. Our injectable product, Byetta, derived from the extract of a lizard, the Gila monster, was the first product approved in that space. That was a really exciting time to advance a first-in-class kind of concept. I guess over the years at Lilly and Amylin, I became passionate about diabetes, so it was a pleasure to say yes, when I was asked to serve as a director on the national board of the American Diabetes Association. I also served as vice chairman of the ADA Research Foundation for a number of years.
After leaving Amylin, my second retirement, I moved to Nashville in 2003 and, with others, started an investment firm, Mountain Group Capital. At MGC, we have been investing in businesses since 2004 including start-up biotech and medical device companies.
Along the way, we came across some interesting technology from the University of Tennessee. At first, the innovation was essentially based on leucine as a potential nutraceutical product. We had some interest in that space because one of our other ventures had been to form a company with Francine Kaufman, MD to develop a diabetes-focused snack bar called Extend Bar. Extend Bars are now available in all the drug stores, and have been well received. Its primary active ingredient is uncooked cornstarch. I was somewhat familiar with the concept of medical foods, or nutraceuticals. As we started studying the leucine idea as a nutraceutical, it became clear to me that its effects were largely centered around a mechanism that was already pretty well known to be similar to the effects of metformin and other antidiabetic medicines. In mid-2013, we decided to pivot the company from a nutraceutical product to developing a human medicine. We decided that we might be able to do more good for people with diabetes by developing a medicine that could make metformin as effective, but with a much smaller dose.
I probably covered more than what you wanted, but it at least gives you a snapshot of how and why I’ve been involved in diabetes for so long.
SF: I can certainly see you have had some great successes, and have changed, probably, millions of lives, certainly with the Amylin products that have been introduced. I know from 1950 to 1995, we only had one oral drug, sulfonylurea. Metformin came out in 1995, even though it was available much earlier overseas. That is one of the reasons we are so successful with our newsletters, because diabetes changes very rapidly with all the new drugs coming out and it is almost impossible to stay current.
JC: Exactly! I try to read every paper I can about new therapies for people with diabetes. That’s why I’m glad you are doing what you are doing. I think it’s not only hard to keep up, but it’s hard to understand how these new therapies fit with each other. They are not always clear. Diabetes is not a homogenous disease. It is a subset of many diseases, as I’m sure you know. The way in which these medicines fit varies widely.
SF: I have a philosophy: people with diabetes are entitled to the same blood sugars as people without diabetes. I think that with all the tools we have, with all these new drugs that we have, there is no reason why anyone should have an elevated A1c.
JC: I would agree with you. I’m not sure I have enough evidence to say it can all be applied, but I agree there is no reason why we couldn’t have diabetes substantially under control with our existing tools.
SF: It boils down to education and knowledge.
JC: And, perhaps, some different approaches from our healthcare delivery system because there are some parts of it that are still activity-based versus outcomes-based. That’s a subject for another article, I’m sure.
SF: Anyway, getting back to the reason for this interview, back in June, there were a number of items presented on the unique combination of a neutriceutical with a drug that has been in the market for diabetes since 1995. It didn’t at first seem like a big deal because it is not a whole new way to treat diabetes, per se. It’s not a new entity that you are combining with metformin, which I call the $3 drug. So your new combination, if it makes it through the FDA process, could have an impact not only on people with diabetes, but even more so on people with pre-diabetes. One day they will say metformin is a treatment for those people with A1cs between 5.7 and 6.4%, but we may have to wait 20 years before that happens.
JC: Not if Ralph A. Defronzo has his way. Ralph has been preaching that for, I’m sure you know, many, many years. I think any evidence that we gather for making metformin easier to use in diabetes will be a potential opportunity for people to explore with pre-diabetes. The problem in pre-diabetes has been the discomfort that is sometimes associated with it, as well as the complicated nature of how to define it. Pre-diabetes is technically not a disease and the FDA cannot approve a drug for something that is not a disease. Now, they have begun to move into that space. I’m sure you’ve seen that with some recent work Novo-Nordisk has done. It is still not 100% certain as to how the FDA would approve a medication for pre-diabetes because there isn’t a primary outcome measure that is accepted as a surrogate, other than the elimination of progression of diabetes, which is pretty hard to do. That would be a very large and complicated trial.
SF: Tell me, what exactly is NuSirt’s technology and how does it work?
JC: How does it work? Very good question. Dr. Michael Zemel has been working in energy metabolism for over 30 years. He was primarily focusing on nutrition and food stuffs, looking at what different foods contributed to energy metabolism and how they all work. After years of research, he essentially came to the observation that a single amino acid, leucine, which is commonly available, was highly likely involved in energy metabolism at the cellular level. What do I mean by that? When the cell is active and energy is circulating in the form of blood glucose, the cell receives that energy and has a varying degree of receptivity to it. When it’s received into the cell, the cell can either reconstruct the glucose into proteins, or synthesize it into other things, or it can store it. In the case of when it has sufficient energy for what it is doing, it will store it. The body’s most efficient storage cell is a fat cell. What he found was that increased levels of leucine caused the body to apportion the energy toward use in muscle cells preferentially versus storage in adipose or fat cells. He thought that was a very interesting way to potentially treat some aspects of the diseases associated with overabundance. That observation was at the cellular level, and he then escalated that up in animal studies.
Ultimately, we actually ran some human studies just looking at leucine with Vitamin B6, and saw an effect in humans with a leucine dose, essentially the same leucine dose that we are studying now with metformin. This was the basis of the nutraceutical product that I talked about that would have been sold over the counter in vitamin shops. However, the reality was that the nutraceutical market is very complicated. There are a lot of snake oil salesmen and charlatans. There is very little validated science. There is some, but not a lot. We decided that, if it worked to add leucine to the body, why not add leucine to a commonly available medicine that worked in the same area? And that was metformin.
SF: It is an interesting technology. Can you foresee this being used with other drugs, whereby you could lower the dose or reduce the other side effects from some other drugs?
JC: Yes, we can. In fact, we have animal evidence now that there are at least two or three other existing medicines that operate in that same cellular area, and we believe we could potentiate their efficacy and substantially lower their required doses. We are in the process of developing patent portfolios for these discoveries. Obviously, my first thought was, “Well, if we are going to develop a medicine, that will require a lot of money. We need to have a patent.”
We do believe that leucine is potentially very useful in other areas, and we have developed a patent portfolio that is very extensive. In addition to patents involving leucine in particular areas for diabetes, we are looking at niacin, for instance, which has been known for a long time to lower cholesterol, but has an unwanted side effect — flushing. In animal models, with the addition of leucine, we’ve been able to achieve an essential similar lowering of cholesterol with 1/20th the dose of niacin, which eliminates the flushing.
Next week, we’ll talk more with Joe Cook, and find out more about exactly how this new drug works and might even be combined with other drugs on the market besides metformin.
Mr. Cook is a principal and co-founder of Mountain Group Capital, Nashville, TN. Mr. Cook serves as Executive Chairman of NuSirt Sciences and on the boards of Castle Biosciences, Diabetes Care Group and Clinical Products. He is a co-founder and serves on the board of Diagnovus.
He is also a founder and Past-Chairman of the Board of Ironwood Pharmaceuticals, Inc. (NASDAQ: IRWD), a biotechnology company in Cambridge, MA where he continues to serve as a director. Also, Mr. Cook serves as a director of Corcept Therapeutics, Inc. (NASDAQ: CORT), a biopharmaceutical company in Palo Alto, CA. Mr. Cook served as Chairman of Amylin Pharmaceuticals, Inc. (NASDAQ:AMLN) from 1998 to 2009 and was Chief Executive Officer from 1998 to 2003. Mr. Cook retired as a Group Vice-President, Global Operations, of Eli Lilly and Company in 1993 after more than 28 years of service. Mr. Cook serves as Chairman of the Board of Mercy Ministries International, Inc. with headquarters in Nashville, TN. He is also a past Chair and current member of the University of Tennessee College of Engineering Advisory Board. Mr. Cook has served on the national board of the American Diabetes Association and is past Chairman of the board of Life Science Tennessee.
Mr. Cook graduated from the University of Tennessee in 1965 where he received a BS in Engineering with High Honors and was a UT Torchbearer.