Take two pills and call me... a compliant pancreas?
Yep, that's the idea behind research a Philadelphia endocrinologist is spearheading with her biopharmaceutical startup Perle Bioscience, established about a year ago to continue the longtime endo's mission to help people with type 1 diabetes become "insulin-independent."
In the eyes of Dr. Claresa "Resa" Levetan, that would be accomplished by taking a pair of pills that would regenerate the insulin-producing islet cells and ward off any immune system attack that kills off those cells and leads to type 1. You may be starting an eye-roll here, thinking "false hope" and "diabetes snake oil." But she doesn't call it a cure, even though it might lead to cutting insulin doses completely, since you'd still have to take two pills a day for the rest of your life. Practicing for 20 years, Dr. Levetan created her startup research group in South Carolina to develop this treatment.
Actually, Levetan's team first developed a drug candidate called Pancreate years ago and sold that as part of a potential $335 million deal to Sanofi in 2010, though nothing has materialized and Levetan says the company's made a decision to pursue that for type 2s only. But instead of turning her back on this research, Levetan has carried on over the past decade, while weaving in enormous empathy for the patient's plight garnered from her many years of practice. To me, it speaks volumes to hear her say the following:
"The pancreas is non-compliant -- not the patient. And when doctors say to me that a patient is non-compliant, that is my signal that the physician doesn't know diabetes. I believe more and more that I learn most about how to help my patients by listening. Most patients with diabetes are sick of being told what to do, when there isn't any one treatment or one bit of advice that fixes the disease."
Exactly! As someone who's done his fair share of griping about doctors using "non-compliant" terminology, I'm a fan of Dr. Levetan's already!
But if that's not enough to give her some street cred in the Diabetes Community, then read on. We were fortunate to catch up with her recently and for the following Q&A about her work -- past, present and where she hopes to see things go in the future.
DM) Tell us about yourself?
CL) I am an endocrinologist with a focused mission on insulin-independence, and I see patients and do research. My first job in diabetes was in 1984 working at the Diabetes Clinic at Grady Hospital in Atlanta, which was after medical school and internship at Emory School of Medicine. I then went back do an internal medicine residency and fellowship in endocrinology. I have done clinical research, basic science research, but have always practiced. Ironically, I have enjoyed practicing now more than ever because I see how despite all of the pumps, sensors, new insulins, etc., the struggles with diabetes are tougher now with insurance companies. I see more patients than ever who have insurance, who still can't afford their insulin and supplies.
I never quit practicing, but spent a number of years making a computer program for patients with diabetes and in a randomized trial, it demonstrated that using a program to developed personalized diabetes goals was more effective than any therapy in lowering A1C. No one would pay for the program or even the cost of color printing the personalized reports generated by the program. I was told over and over again, even by those at managed care companies, that I would be much better off making a drug because people pay would pay for that rather than a personalized computer report... so I did.
Currently, I have a solo practice with a fabulous diabetes educator, Susan Pierce, who has type 1, and who's been with me for more than a decade and has been very involved in our research.
You've got fans, like Dr. Irl Hirsch who describes you as "one of the most creative" he's met. What's your secret?
I am definitely more of a right-brained person than a left. I learned pretty early that my biggest mistakes, though painful, always turned out to lead me in directions that I would never have dreamed of going. So when I hit a wall these days, I actually see it as a good thing after the initial jolt.
A big paradigm shift in my whole thinking in diabetes came to me in the '90s when were doing studies for MiniMed on their new glucose sensors. I learned when I wore a sensor that my glucose levels never went above 103 compared to my patients on pumps with A1Cs of less than 6.5% who had glucose levels from 40 to 400. It took me a while to figure out that diabetes was not just about insulin. This experience really made me understand how little I knew about type 1 diabetes. It was around that time that the hormone amylin/pramlintide/Symlin that is co-secreted with insulin in equimolar concentrations had been discovered and was being studied and I did everything I could to better understand what amylin did since the studies were clear that it did not lower glucose.
My team did studies showing that when you gave pramlintide with insulin before meals in type 1 patients, the insulin requirements dropped significantly and glucose fluctuations also were lower. We also showed that amylin suppressed glucagon that is released from the alpha cells, which in type 1 was too high after meals leading to release of extra glucose by the liver.
Next I began looking at other islet hormones and how they all were interconnected to normalizing glucose. It was pivotal for me to begin learning about the other islet hormones and how each contributes to normalizing glucose. Although insulin is certainly life-saving, each of the five other islet hormones plays a role in keeping glucose levels normal. I no longer saw diabetes patients as non-compliant -- as I hear my colleagues call them.
How does that mindset translate into your role as a researcher for a D-cure?
I have been a collage artist and sculptor since I was young, so I see solving scientific problems perhaps a little differently from some scientists. I see the diabetes research in type 1 diabetes a bit like the parable of the blind men and the elephant, where each blind man describes the part of the elephant he is touching as completely different than the others. Diabetes researchers have many different focuses -- whether it be working on the inflammatory response that occurs, the immune attack, lack of beta cells, regeneration of beta cells, islet dysfunction that follows beta cell loss, etc. I believe that everyone in the field, whether their studies are positive or negative, brings us closer to understanding the big picture.
What's your current research focus?
Our hypothesis is that that diabetes is NOT JUST a disease of autoimmunity, but one of 1) autoimmune attack on beta cells and 2) the lack of the human pancreas' ability to regenerate beta cells, even when an immune agent is given. Beta cell turnover in mice is much faster than in man. Thus, despite more than 60 recent studies using all types of therapies that have reversed diabetes in type 1 mouse models, none have shown the same success in man. I believe that insulin independence will result from combination therapies -- immune therapy in combination with a beta regeneration agent. (See this article of mine: 2013 Levetan Pierce Distinctions Between Islets of Mice and Men)
And that led you to founding the research firm Cure DM a decade ago and eventually selling Pancreate to Sanofi...?
It's similar to the studies conducted by Frederick Banting of ligating the pancreatic ducts in dogs and collecting the secretions, which later became known as insulin. We're doing those same studies today: the same genes are expressed to protect the pancreas by regenerating new islets from pancreatic ductal tissue. What we now know is that acute injury to the pancreas results in regeneration genes becoming present to preserve the pancreas. The human genome and proteome became available and accessible, and it became easier to figure out which genes are turned on when the pancreas is injured. These genes transform pancreatic ductal tissue to islets.
Our team made a discovery of the gene and the portion of the protein that results in transformation pancreatic ducts to islets. We have new patents based on our discoveries of which genes and peptides within the gene protein are expressed when there is acute injury to the pancreas and are responsible for transforming pancreatic ducts to islets.
When we licensed our first drug HIP (Human Islet Peptide) to Sanofi in 2010, studies proceeded in type 2 patients. I was extremely upset, asking why studies wouldn't go forward in type 1 and naively saying "just combine HIP with an immune agent." I learned that there was no model of using a regeneration therapy with an immune agent to protect the new islets, and that wasn't so easy from a drug development standpoint. Thus, our next venture Perle Bioscience was formed.
In your work now, you use the phrase "reversing diabetes" quite a bit -- haven't you heard all the feedback from people who despise that term? How do you approach that issue?
I agree -- people with type 1, families and friends have been so terribly disappointed, and I have been shot down by so many people for using the words "cure" and "reversing" diabetes. So, if I do that, please stop me. My focus is insulin independence for type 1.
Has your goal changed at all with Perle?
Our goal in our first study is to demonstrate that an immune agent and regeneration agent can preserve beta cells and result in insulin independence. We have a sponsored research agreement with Yale University which is testing our new therapies to determine how effective they are in generating new islets from ductal tissue. The Yale team has a great deal of experience with the gene therapy that we are using. We are also collaborating with many other scientific teams from around the world from Italy to Israel working towards insulin independence.
Tell us about the PRL001 and PL002 drug compounds you're working on?
PRL001 is a combination of two FDA-approved therapies -- cyclosporine, which had the highest rates of insulin independence in the 1980s, and a proton pump inhibitor, which has been shown to increase beta cell mass in patients with diabetes. We are planning for a multi-center Phase 3 trial in early 2015. If we don't get FDA approval for studies in the US, we are set to start in Europe.
PL002 is a combination of our new REG peptide with an immune agent.
We are developing new therapies, which he hope to show as we did with our previous REG peptide, to be much more potent than proton pump inhibitors in transforming ducts into new islets for use in patients with new and existing type 1 patients with an immune protectant. One REG peptide has already shown a 27% rise in C-peptide among patients with type 1 diabetes for 20 years, but unfortunately without an immune agent, the results were not permanent.
How does your work at Perle fit in with other projects, like the DRI and JDRF encapsulation projects or beta cell regeneration?
We hope to have patients make their own new islets (which contain new populations of beta cells) and combine our regeneration therapy with the lowest possible dosage of immune suppressant, so no beta transplants or encapsulation is needed. All research moves the field forward.
What else would you want the D-Community to know about your work?
This video sums it up best for me:
Just know that I made a promise to Louis Cocco (boy in the video) and I plan to keep that promise. Nothing is stopping me!
Thanks for all your doing, Dr. Levetan! We look forward to seeing where your research goes and hopefully helps bring us closer to insulin independence down the road.