In Part 2 of this exclusive interview, Dr. Robert Geho discusses the Phase 2b study which focuses on adding Diasome’s HDV to a leading pre-meal fast acting analogue.
This is the second part of a two-part interview. Click here for Part 1.
To view this interview as a video, click here.
Steve Freed: So you’re about to start early Phase 3 trials?
Robert Geho: We’ve been approved or enabled for Phase 3 but what we’re doing instead of that [is] a Phase 2b study. The primary reason we’re doing a 2b instead of a 3, in subjects with type 1 diabetes, is that we have been enabled for two different commercial formulations by FDA. One is what they call a pre-mix. That would be if we had a partnership with an insulin producing company, we could provide them with our liquid nanotechnology and they could add it to their insulin and vial it at their own facility. That would be a pre-mixed product. We’ve also though, and I think this is a first in the pharmaceutical industry certainly with diabetes therapies, we’ve been approved for Phase 3 testing as an admixture. That’s where we take a commercial vial of insulin and our material, HDV, and at the clinical site, the pharmacist will add about a milliliter of our liquid nanotechnology to a standard 10ml vial of liquid insulin, and it will mix together in a very straightforward way on a once per vial basis and that new vial then will be handed to the subjects in the clinical study.
Steve Freed: Do you see this going as far as, obviously, partnering with a large insulin company would be the best choice? You don’t actually see where pharmacists are going to add an ingredient to a bottle of insulin?
Robert Geho: So, it’s an interesting commercial question that we haven’t resolved yet and that’s frankly why we’re doing a 2b instead of a phase 3. If we were going into phase 3, we would have had to have made that decision. Do we want to do it as an admixture or a premixture? But the fact that we can do it as an admixture, technically and from a regulatory point of view, gives us a lot of flexibility in terms of how we look at our Phase 3 program. It also means that theoretically, while as you say, Steve, doing a partnership with one of the insulin companies would be the obvious commercial path. We also have the opportunity to talk to other companies that would like to be in the insulin business but find it difficult to break through. Having an admixture candidate that is truly insulin agnostic, meaning it’s designed to work with all forms of commercial insulin, gives us a lot of commercial flexibility for our stage of development.
Steve Freed: So, a person adds this mixture or pharmacist does it for your study. What are the benefits they are going to see because of the combination of a mixture of insulin? With what kind of insulin do we see this being used? Long acting, rapid acting? Where is it best used?
Robert Geho: So, it can be used in any form of insulin, but our Phase 2b is going to be focused on the use of HDV plus a leading pre-meal fast acting analogue. Like Humalog or Novolog.
Steve Freed: When a person does this, let’s say they’re starting out with an A1C of 8 and now they have this mixture, and do nothing different. What will their A1C be over a period of 60-90 days?
Robert Geho: Well, we’re hoping certainly for a significant reduction in HbA1C. So the clinical study is set up to show we hope for a reduction of at least 0.5% so a half a point drop of HbA1C from baseline. If we’re able to re-establish the liver’s normal function of mealtime glucose uptake or storage that should have a significant effect on peripheral blood glucose which will of course bring down HbA1Cs. The other corresponding benefit is if the liver is now storing a significantly higher amount of glucose with this therapy than it can with regular Humalog, Novolog, Apidra, Humulin, or Novolin, the liver can release that glucose as need to counteract hypoglycemia in response to glucagon.
Steve Freed: That’s interesting because you’re saying that you’re going to increase the storage of glucose. That means that you’re probably going to gain weight. Now insulin causes weight gain anyways. How is this going to affect weight?
Robert Geho: So, our hope is that weight is a secondary endpoint in the Phase 2b study, because if we can lower the demand on peripheral blood glucose in fat and muscle, in other words if we can bring down people’s overall insulin requirement, because we’re sequestering 50% of the glucose that they eat in their liver, which is where it’s supposed to be in a healthy individual, then there is going to be less demand for glucose uptake in the periphery which is directly implicated in the weight gain issue, seen with peripheral insulin administration. So we’re really hoping that in addition to a reduction in A1C and hypoglycemic events that we do show an improvement in weight, simply because we are now sequestering all of this glucose back in the liver where it should be as it is in a healthy individual.
Steve Freed: So, how much have you seen as far as a reduction in the use of insulin?
Robert Geho: So our longest dosing with the injected dose form to date is two weeks in a randomized double-blinded study in type 1s, so the Phase 2b is going to be a 6 month study and we’re hoping to see in that study, if we could reduce overall insulin requirement by 20-25%, that would be a big success in that regard, from our point of view.
Steve Freed: What have you seen in animal models?
Robert Geho: We haven’t tested it long enough in animals to see a reduction in total insulin requirement.
Steve Freed: What about reduction? Obviously if you’re using less insulin, there’s a good chance that you’re going to have less hypoglycemia?
Robert Geho: The hypoglycemia we think should be handled both by a reduction in peripheral insulin requirement and most importantly, in an increase in hepatic glucose storage at the time of a meal, so that that glucose can then be released. So in a multi-week dog study that we did in Edmonton, several years ago, even in animals who had been pancreatectomized, we basically eradicated hypoglycemia on the weeks when they were on HDV insulin, compared to the weeks when they were on regular insulin without this hepatic targeting.
Steve Freed: One of the things, when it comes to new products, and I’ve seen this happen. If you’re a small company compared to some of the big ones, Novo and so forth and you have a new product that’s very effective. Getting the information out there to the family practitioner can be very difficult. I’ve seen small companies waver along hoping to be bought out. How do you feel that you are going to be able to market this? Let’s say you’re very successful. How are you going to market it?
Robert Geho: So there are a couple of different things. First from a clinical point of view, my understanding in terms of the history of clinical development over the last, let’s say 30 years, since the beginning of the biotech age with Humulin and Novolin, is that no insulin, save one, has beaten another insulin in a head to head insulin challenge in a long term, for instance a Phase 3 study. So Humalog did not beat Humulin, in terms of A1C and hypoglycemia. Novolog didn’t beat Novolin in its Phase 3 program. That’s if you go to the package inserts for both of those drugs, the A1C responses between both groups. The only one that’s ever beaten the reference insulin in a head to head challenge is the pegylated Lispro or pegylated Humalog that was part of the Imagine studies at Eli Lilly. That by the way is a hepato-preferential form of insulin, so they pegylated, they put polyethylene glycol on Humalog to increase its circulatory time with the strategy of having that hit the liver more often than not. That is the only one that has beaten Lantus or has beaten the reference insulin in terms of HbA1C in fact. So if we’re successful by virtue of making Humalog or Novolog hepato-preferential and lowering both HbA1C and decreasing the incidence of hypoglycemic events, I think every type 1 patient is going to know about that very quickly and want to be treated with that form of insulin. So as a type 1 myself, I know full well the challenges of aggressive insulin therapy. If I have something that I can add very simply to an already approved insulin, that is inexpensive and easy to use and reduces both HbA1C and hypoglycemia, that’s not a very difficult sales proposition as you know especially in the type 1 community. However, I also think that we’re going to have to be very sophisticated from a commercial point of view, because the PBMs are much more aggressive now than they were even 5 years in terms of dominating that discussion. So we will have to be out in front of that issue in dealing with insurance companies, the leading PBMs, explaining the physiology, explaining what we’re doing, keeping them up-to-date on all of our clinical progress over the next 1-2 years and we have to be very intentional about that and we have a strategy underway to make that happen.
Steve Freed: When do you expect to start, time frame, and how many people are you going to start with and how many locations?
Robert Geho: So, we have an investigator meeting scheduled for the middle of May, we’re hoping that the first patient will be dosed before the end of the second quarter of this year. We’re going to enroll about 175 subjects and plan to complete 150 subjects. Probably, be 6-9 months of enrollment time, and 6 months of dosing, so it’s about a 12-15 month process from start to finish.
Steve Freed: You finished your safety study?
Robert Geho: From the FDA’s point of view, we are completely done with all of our toxicology testing.
Update: Diasome Pharmaceuticals, Inc., patient dosing has commenced in its ISLE-1 (“InSulin Liver Effect – 1”) Study, a multi-center, double-blinded, randomized controlled Phase 2b clinical trial of HDV Insulin, a first-in-class liver hepatocyte targeted form of commercially available rapid-acting insulin. The goal of the ISLE-1 study is to demonstrate that people with type 1 diabetes can achieve better and safer glucose control when a portion of their injected insulin is able to mimic the normal action of insulin from the pancreas during a meal.” The ISLE-1 study is expected to enroll up to 200 subjects with type 1 diabetes at 25 sites, randomized in a 2:1 ratio to either HDV added to a leading commercial pre-meal insulin or that commercial insulin without HDV. The study will evaluate the effect of HDV as an insulin additive over six months of dosing on a variety of standard diabetes outcomes, including overall glycemic control.