Steve Freed: Thanks again for taking time out to answer some questions. What did you take away from the ADA as the most interesting?
Dr. Alan Moses: From a Novo Nordisk perspective, we were very pleased with how our phase 3 insulin degludec data, as well as data on Victoza, were received. Data presented showed that patients who switched to treatment with once-daily Victoza experienced greater reductions in blood sugar when compared with other commonly used treatments for type 2 diabetes (sitagliptin and exenatide). We also were pleased with the response to our data which showed that the addition of Levemir to treatment with Victoza helped additional patients reach the A1c goal of <7%. It's also important to note that on Victoza alone, 61% of trial patients reached the <7% target). This data suggest that adding basal insulin to Victoza can provide benefit for additional patients with type 2 diabetes.
SF: And at the meeting, the president's poster session, Novo presented the results of the use of liraglutide with type 1's. Can you just kind of review the importance of this poster?
Dr. Moses: Actually this work was not conducted or sponsored by Novo Nordisk. This study was conducted and presented by Paresh Dandona's group from State University of New York, Buffalo. Based on the nature of the trial, Novo Nordisk cannot comment on these data.
SF: Is liraglutide plus insulin a possible combination that Novo might be looking at down the road?
Dr. Moses: Neither of these approaches is currently supported by the Victoza label. Novo Nordisk continues to conduct research in hopes that treatment with Victoza can help additional patients living with diabetes but as of today, Victoza is only indicated for the treatment of adults with type 2 diabetes. To be clear, while we presented data examining adding basal insulin to treatment with Victoza, the sequence was different than what was studied by Dandona and colleagues. The Novo Nordisk sponsored data may raise the possibility that Victoza can be used across an even wider spectrum of diabetes but, of course, this is pending a proper development program and regulatory review by the FDA.
SF: So is it possible that there can be a pen that actually has both in it so that it would be one injection?
Dr. Moses: Yes. A pen of this kind is currently in phase three development.
SF: If you had to pick the best candidates for liraglutide, what type of type 2 patient would that be? Someone that has had diabetes for 25 years, who has high A1cs and all kinds of complications, or maybe someone newly diagnosed with an A1c of six and a half or seven?
Dr. Moses: The catalog of Victoza data includes one monotherapy trial which included individuals with relatively recent onset of type 2 diabetes (~5 years). These data suggest that Victoza can be effective when used relatively early in the course of disease, meaning after metformin failure. For those individuals who have not responded sufficiently to metformin, which unfortunately is too many, the addition of Victoza is a very appropriate next step, which brings a large percentage of patients to goal, with a low rate of hypoglycemia and no weight gain. In fact, Victoza treatment is associated with weight loss.
Victoza's clinical trial program, LEAD, suggests and supports that Victoza can be used across a wide spectrum, including being very effective in individuals who have failed two OADs, and even compared to insulin glargine. Due to its mechanism of action and that of other GLP-1 receptor agonists, to improve beta cell function or improve the beta cells' ability to recognize glucose concentration and increase insulin secretion, it makes sense to use Victoza relatively early, when you can potentially preserve beta cell function for the long term.
SF: How confident are you with the safety of liraglutide as far as being associated with pancreatitis and thyroid cancer, which is part of, the label?
Dr. Moses: Novo Nordisk stands behind Victoza as a valuable treatment option for those living with type 2 diabetes. However, with all medications there are associated risks. In conjunction with an FDA post-marketing requirement, Novo Nordisk, in association with the American Thyroid Association, is doing a case series registry examining all cases of medullary carcinoma that develop in the United States to determine if any of those are associated with exposure to a GLP-1 receptor agonist. We have active studies examining the risk of thyroid cancer, but at the moment we have seen no evidence of a relationship.
SF: With liraglutide, it has so many mechanisms of action, working on the liver, working on the pancreas, working on the brain, is there a particular one that you feel is a major mechanism of action for liraglutide, or is it just a little bit of each?
Dr. Moses: That's a really good question, and I cannot give you a definitive answer. Victoza does have multiple actions. The liver effect is probably indirect, a function both of increased insulin secretion -- glucose dependent insulin secretion, and as a function of decreased glucagon secretion. In regard to the brain or even the peripheral nervous system and its effect on things such as satiety, appetite and how quickly one feels full, there definitely seems to be something going on there and I think we need to await additional studies focused on mechanisms of effect.
SF: And that kind of leads me to the next question: is Novo looking at liraglutide in non-diabetics for weight loss. Are you looking at that with certain types of diets? I have a physician that's been very successful using it as a weight loss product with a low carb diet. Is that something that you're doing research on?
Dr. Moses: As Victoza is only appoved for the treatment of adults with type 2 diabetes, currently diabetes is our primary focus. That said, Novo Nordisk is currently conducting phase three clinical trials assessing the use of liraglutide as a treatment for obese adults without diabetes.
One of three trials in the phase three program has been completed and a phase two study has been published in The Lancet.
At this year's ADA, a poster that outlined the results of one of those phase three studies was presented. The goal of the study was to determine if liraglutide would be able to maintain hypocaloric diet induced weight loss over a one year period of time. It was interesting because it looked first at individuals who had lost at least five percent of body weight on a severely calorically restricted diet. So, in other words, in order to be randomized, the treatment with liraglutide versus placebo, you had to lose five percent of your body weight first.
About 75 percent of the individuals who entered the trial actually got to the point of randomization. That is, they had successfully lost 5% of body weight (before drug treatment), which is a very high percentage for diet-induced weight loss. Indeed, they had achieved nearly a six percent weight loss. Not only did liraglutide treated patients maintain weight loss over a subsequent year, but they lost an additional five and a half percent of body weight.
SF: I presume that you're going to have to go through the cardiovascular studies to even have the FDA even look at it?
Dr. Moses: We have a cardiovascular study underway for Victoza called the LEADER Trial. It is part of our post-marketing requirements with the FDA to demonstrate cardiovascular safety. The hope, of course, is that that will not only demonstrate lack of harm, but also potential benefit. It will be interesting to see how the regulatory agencies look at those data, assuming a positive outcome, vis a vis the obesity indication and the higher dose to be used for that indication.
SF: I had read that GLP-1, the natural GLP-1 in our bodies is activated by a certain nutrient. Have you seen anything like that, whether it's activated by fats, or carbohydrates?
Dr. Moses: Yes, there's a lot of interest actually, but I am far from the expert on this, as to whether certain nutrients actually have a specific effect on GLP-1 secretion from the L cell. A number of companies are actually looking to identify agents, pharmacologic agents, which might in fact stimulate or potentiate GLP-1 release from the L cell. So that's a very active area of investigation.
SF: Can you kind of share with us where you are with your new insulins, your long acting and your more rapid acting insulins, as far as where they are as far as submitting to the FDA?
Dr. Moses: We do indeed have new insulin in development. A lot of information about our new ultra-long acting basal -- we call it insulin degludec -- was presented at the ADA this year, both in oral presentations and a number of posters. We also are developing insulin degludec in combination -- and I mean the first true fixed combination insulin product, where insulin degludec is combined with insulin aspart or NovoLog. The physical chemistry of the insulins actually allows them to be combined without adversely affecting the pharmacokinetics or pharmacodynamics of either. That creates a very different insulin profile than has been possible with prior formulations of so-called mixed insulins in the past, whether they be human mixed insulin or analog mixed insulin, such as our own NovoLog Mix 70/30.
Insulin degludec, the ultra-long acting basal, is at the end of its phase three development program. We are putting together the regulatory dossiers to submit that to the Food and Drug Administration, to the European Medicines Authority and to the authorities in Japan, PMDA, late this year. And the hope of course is that these files will have a very positive review by the regulatory agencies.
This insulin is completely comparable to insulin glargine, in terms of its glycemic efficacy, but the goal is to create a basal insulin that has an improved safety profile and a lower rate of hypoglycemia. Insulin degludec certainly appears to have that compared to insulin glargine, particularly as assessed by nocturnal hypoglycemia. In addition, because of its very long half life, insulin degludec affords the patient a greater degree of flexibility in terms of when they can administer the insulin; should they be delayed with an injection because of a social engagement, whether they are traveling, whether they forget their insulin. Because of its very long half-life, there's a safety margin with insulin degludec in regard to time of administration, and we've demonstrated this in a clinical trial. Insulin degludec should allow patients to have a lot more freedom of action in regard to their basal insulin administration.
For the combination of insulin degludec and insulin aspart, this should be viewed as just a better form (or formulation) of insulin in regard to those individuals, whether it be by culture, geography -- that is, certain countries, or lifestyle -- that would be best served by having the bolus combined with the basal. This way you can take it once or twice daily before the largest meal(s) of the day, and get not only the bolus component of the insulin aspart, but a very, very stable basal component which dramatically reduces the risk of hypoglycemia compared to current pre-mixed insulins. And when I say dramatically, I mean more than a 70 percent reduction in nocturnal hypoglycemia compared to currently available analog mixed insulins.
SF: What is the duration of the new insulin?
Dr. Moses: The biological activity, that is, its pharmacodynamic profile, is greater than 40 hours. Its half life is 25.4 hours and that is twice as long as insulin glargine.
SF: Does Novo have any other new drugs in the pipeline for diabetes or first in class drugs?
Dr. Moses: We have lots of other projects underway as well that are in earlier stages of development, including both oral basal insulin and oral GLP-1.
SF: That sounds exciting. Pre-diabetes obviously is a huge epidemic. The numbers keep going crazy, especially with children. Are you doing anything to look at liraglutide to get it possibly approved for pre-diabetes?
Dr. Moses: Well, that's a very interesting question. Of course, the challenge is that there's no regulatory indication for pre-diabetes at the moment, so that creates an interesting challenge in terms of designing a program for that indication.
SF: Can you share what you know about the cardioprotective effects of liraglutide?
Dr. Moses: Let's first look at the class of GLP-1. Some of these changes seem to be specific to GLP-1 and not to DPP-4 inhibitors, at least by work that Dr. Drucker's laboratory and colleagues in Toronto have evaluated. And if you look at animal models where both liraglutide and exenatide (and other GLP-1 receptor agonists) have been studied, it seems to be a class effect. What happens is that if you induce a myocardial infarction in a rodent, by ligating the coronary artery, GLP-1dramatically reduces the amount of myocardial injury that occurs and increases the survival of the animals. That's a pretty dramatic finding.
In humans, there have been studies looking at native GLP-1 in the coronary care unit post-acute MI or with congestive heart failure, and under both circumstances, GLP-1 seems to improve the outcomes. We know that there are plentiful GLP-1 receptors on the endothelium and probably in myocardium as well. However, we don't fully understand how those receptors are doing what they do.
From a long term perspective, we do know from our clinical trial data that liraglutide reduces systolic blood pressure. I should mention, however, that blood pressure language is not part of the FDA label for liraglutide although it is mentioned in the European label.
SF: What do we know about liraglutide and its effect on beta cell apoptosis and regeneration, which has only been studied in animals?
Dr. Moses: In animal studies, rodents primarily, liraglutide increases the development of beta cells and it inhibits the effects of agents that produce death of the beta cell. It looks very promising. The challenge from a clinical perspective is that the turnover of rodent beta cells is actually moderately high, whereas the turnover of human beta cells is extremely low.
SF: Thank you, again, for your time.
Alan Moses received a BS from Duke University and an MD from Washington University School of Medicine prior to training at Barnes Hospital in St. Louis, MO, the National Institutes of Health in Bethesda, MD, and Tufts-New England Medical Center in Boston.
Dr. Moses is board certified by the American Board of Internal Medicine and has subspecialty certification in Endocrinology and Metabolism. He is a Fellow of the American College of Physicians. In 1998, he was appointed Senior Vice President and Chief Medical Officer of the Joslin Diabetes Center, a Harvard-affiliated independent clinical and research facility and was appointed to the rank of Professor of Medicine at Harvard Medical School in 2002. During his tenure at Harvard, Dr. Moses was involved in basic and clinical research, patient care, teaching of medical students, housestaff, and fellows, and medical research administration. He co-founded and co-directed the Clinical Investigator Training Program at Harvard Medical School and the Massachusetts Institute of Technology HST Program.
In April 2004, Dr. Moses joined Novo Nordisk, Inc as Associate Vice President for Clinical Research and Medical Affairs - Endocrinology and in 2007 was named Chief Medical Officer, North America. In January of 2008, he was named Corporate Vice President and Global Chief Medical Officer. In this role, he is involved in the full spectrum of the diabetes focus of Novo Nordisk from drug discovery, through drug development, brand messaging, and the implications of diabetes for the company and for patients, healthcare professionals and for healthcare systems.
He has written over 100 papers and articles on the treatment of diabetes, is an Editor of the Fourteenth edition of Joslin’s Diabetes Mellitus, and has been recognized both locally and nationally for clinical care in diabetes and for his research in diabetes and growth factors.
Copyright © 2011 Diabetes In Control, Inc.