Pape: Hi. I’m Joy Pape with Diabetes in Control. And we’re here today, at the ADA 2018 Scientific Session. I’m happy to introduce you all to Dr. Jeff Emmick, Vice President of Product Development at Lilly Diabetes.
Emmick: Hi, Joy.
Emmick: Thank you.
Pape: Yes. So, what does Lilly have in its pipeline?
Emmick: Well, exciting. Lilly is actually the only pharmaceutical company in diabetes care who has the full breadth of products when talking about a wide range of therapies crossing the orals and our partnership with Boehringer Ingelheim, the insulins, and of course our insulin heritage dating back to the 1920s, and then incretins. So, very exciting to have that wide range of opportunities for patients. From a portfolio perspective, let me start with some of the new data and ongoing work with our marketed products and then I’ll move back to some of our phase 3 opportunities. We announced yesterday some phase 2 data on Trulicity and specifically it was our Dulaglutide 3 and 4.5 milligram program. The idea there was to explore higher doses of Trulicity than are currently approved. So, Trulicity is approved up to 1.5 milligrams but we wanted to see whether there’s an opportunity to gain additional A1C control and weight loss at those higher doses. We released that data in an oral presentation yesterday along with the press release that you may have seen and it looks very promising. We saw additional A1C reduction at those two higher doses as well as additional weight loss. And we have announced that we have actually moved that program into phase 3, so we will move it forward now for phase 3 clinical testing and hopefully have an opportunity potentially bringing those higher doses to market.
Now, why is that important? And the idea is patients might do well for a period of time on the 1.5 milligram dose and then perhaps they need something additional for their control, so the idea here would be that then perhaps they don’t have to transition to another product. They can stay on Trulicity and maybe not add another product or switch. So, certainly something that could be in the interest of the patient, convenient for patients.
We have also announced, although no data here, that the other important ongoing work with Trulicity is our REWIND cardiovascular outcome study. We got a lot of questions about REWIND. We expect that trial – an event driven trial so we don’t control when it hits its final event number — but we’re closing in on 1,200 events and expect release results from that study later this year. Switching over to our orals, Jardiance. Of course as you probably know Jardiance was the first diabetes therapy to actually demonstrate cardiovascular risk reduction with significant reduction in cardiovascular death. I’m very excited about the opportunities we have with Jardiance. We have recently announced that we’ve started two EMPA-REG heart failure studies, one in called HFpEF or preserved heart failure and one in reduced heart failure HFrEF. So, we have two ongoing large outcome studies in heart failure. We have two studies called the EMPERIAL [heart failure] Studies that actually look at heart failure in terms of exercise outcome, so a six-minute walk test. And then we’ve very recently announced the onset of a chronic kidney disease study with Jardiance. So, five fairly large studies focused on heart failure and renal disease all based on some of the secondary outcomes of the EMPA-REG trial that we reported a few years ago.
That kind of encapsulates our marketed products. And then moving to the portfolio, we’ve released new data at this meeting at the ADA 2018 on our ultra-rapid insulin lispro or Early as we call it. We released data from three phase 1 studies, a type 1 and type 2 study with multiple daily injections and then the type 1 study with a pump. And what we show with those is consistently faster onset both in terms pharmacokinetics and pharmacodynamics, in terms of blood glucose control and actually a faster offset as well. And so, we see a shift of the entire curve compared to Humalog, to the left. Very important is we think about flexibility around real-time, those MDI studies actually look at dosing 15 minutes before or at and 15 minutes after a meal, and we saw reductions across all three time points. Provides potential greater flexibility for patients around meal dosing, because as we know sometimes patients dose and then for whatever reason, maybe they don’t eat or don’t eat as much as they had anticipated and then they’re at risk of hypoglycemia. The faster offset we believe will be important as well because it is a mealtime insulin and we don’t want the insulin hanging around too long to induce potential postprandial hypo, so very excited with that data. We have announced those. That product is actually in phase 3 clinical testing as well in both type 1 and type 2 patients, and we’ll be seeing data from those trails the end of this year as well.
Moving onto another phase 3 opportunity, nasal glucagon, we get a lot of questions about. I think most everyone knows about today’s glucagon emergency kits but they’re fairly difficult to use, require reconstitution; it’s typically not the patient who is giving themselves the glucagon and it can be — it might be a trained caregiver but it might just be a friend or a bystander. And we know from some studies that have been done in the past, looking at the use of those products that it is very difficult. Many times the patient doesn’t actually get the product, maybe it’s not reconstituted accurately or someone is just afraid to give the injection. Our nasal glucagon product which has finished phase 3 testing as a ready-to-use powder formulation. Basically stick into one nostril, hit the button, it delivers your dose. We’ve already shown data to show that it acts very similarly to the injected version, easy for anyone to give, and we’re very excited. There’s tremendous underuse of the glucagon E- kit because as all physicians know that actually the recommendations are certainly any type 1 patient, they’re on insulin, they should have the E-kit. And actually type 2 patients on insulin should have access to an E-kit, but tremendously underutilized and very difficult to use today, so we are excited about that product. As I mentioned, we have finished phase 3 testing. We’re actually in the middle of preparing a submission and we’ve been working very hard on the commercial manufacturing of that product which we acquired from Losemia several years ago. And we’ve announced we plan to do a submission for that product this year as well. So, that’s a quick look.
We also released some data, Humulin R U-500, that was the first highly concentrated human insulin available on the market. And what we know about that product is that about 25% of patients actually use it in pumps but no pump is actually designed or callibrated for a U-500. And so, what we’ve been doing in a partnership with in Insulet and their OmniPod System is working on a pump system dedicated for U-500/. And we’ve revealed results from the first large trial of U-500 in a pump, what we see was greater hemoglobin A1C improvement with a pump versus MDI use, somewhat what we expected to see. Some increase in nocturnal hypo rate but overall hypos were pretty comparable between the MDI use and the pump. And it just boils straight the need to tailor the pump use moving down the road, but it will provide an important an important option for those patients who are currently using or would like to use U-500 in the pump setting. So, that’s a quick snapshot of the portfolio, at least the later phase portfolio. And we’re extremely excited about both what we have in terms of opportunities for patients now and what’s coming down the pipe.
Pape: Wow. That’s a mouthful, that’s an earful, and that’s Lilly. Lilly Diabetes, always keeping up and doing what’s best for the patient.
Pape: So, are you doing any studies of using the GLP-1s and the SGLT-2s?
Emmick: So, we actually already reported results from a study done as a part of our Trulicity program called AWARD-10. And that study was GLP added onto a background of SGLT-2 Inhibitors. So, exactly the question you’re asking, we know that with the increasing use of SGLT-2 Inhibitors and the demonstrated cardiovascular benefit in the case of Jardiance that there will be increasing use of the oral agent but eventually many patients will progress on to needing an injectable. So, we thought it was an important question. In fact, we were the first company to actually report on in a full phase 3 study that showed in this case Trulicity added on top of any background SGLT-2 Inhibitor, so they could come in on their background therapy. They were optimized on that therapy for a period of time and then randomized to placebo or Trulicity. What we showed in that study as you would have expected was further increase in A1C reduction when you added the GLP, further reduction in weight and really no significant difference in hypo events, so demonstrated both the efficacy of adding GLP-1 to an SGLT-2 Inhibitor as well as the safety. So, those results have been reported and submitted to regulatory authorities for labeling as well.
Freed: And I’ll just add one. Did you see any benefits, analgesic effects, of weight, A1C when you combine those two and the improvement in the risk for death and for cardiovascular disease?
Emmick: So, to the first question about whether the effects where synergistic, no evidence of synergism, probably slightly more than additive in terms. If you look at the individual effects of, let’s say, in SGLT-2 and the individual effects we’ve seen with Trulicity. Additive to slightly less in additive, not synergistic but certainly additionally once the end weight reduction as you would have — as we expected. In terms of cardiovascular events, of course this was a typical phase 3 diabetes study. And so, that would have to actually be tested in a full-scale cardiovascular outcome study. And it is a question of interest, given that Jardiance has demonstrated a cardiovascular event reduction and has a label for that. Victoza has as well. We’ve got the ongoing REWIND trial that we will see later this year. So, I think the big outstanding question is would the two together provide additional cardiovascular benefit versus each agent alone. It’s a great question. No one currently has proposed such a trial. It would be a very large trial. I think the other thing that’s becoming increasingly obvious to us as we have more classes that show a cardiovascular benefit, the challenge of showing additional benefit on top of those agents in large scale trials is going to become increasingly difficult. And so, I think that’s something important from kind of an agency perspective as we look at how we design cardiovascular outcome trials in the future. We’re going to have to consider that, because it becomes unethical to exclude something that’s showing a benefit in the placebo or standard of care arm, but it is a great question and one that remains unanswered.