Zealand release positive topline results for pivotal phase 3 dasiglucagon trial – September 18, 2018

Zealand announced today via press release and conference call positive results for the primary and key secondary endpoints of its pivotal phase 3 trial (n=168 patients with type 1 diabetes; announced December 2017; completed May 2018) comparing dasiglucagon’s safety/efficacy vs. placebo and Novo Nordisk’s GlucaGen (reconstitution kit) when administered as a single-dose hypoglycemia rescue treatment.

On the primary endpoint of time to plasma glucose recovery (defined as first increase in plasma glucose of ≥20 mg/dL from baseline without administration of rescue IV glucose), median time to blood glucose recovery with dasiglucagon (n=82) was 10 minutes (95% CI=10-10) – significantly (p<0.001) faster than placebo (40 min, 95%CI=30-40; n=43) and modestly faster than GlucaGen (12 min, 95%CI=10-12; n=43).

During Zealand’s conference call, CMDO Dr. Adam Steensberg defined the “key” secondary endpoints of the trial: plasma glucose recovery (same definition as the primary endpoint) and glucose change from baseline within 30, 20, 15, and 10 minutes after glucagon injection – the first two of 17 secondary endpoints listed on ClinicTrials.gov. On the former, 99% of subjects recovered from insulin-induced hypoglycemia within 15 minutes with dasiglucagon, compared to 95% with GlucaGen and 2% with placebo (p<0.001). Dr. Steensberg emphasized the implications of this result, extolling it as, “outstanding compared to other rescue products in development” (more on that below). Dasiglucagon did not raise any independent safety concerns, and nausea and vomiting – both known side-effects of emergency glucagon treatment – were comparable between the dasiglucagon and GlucaGen groups (55% vs. 53% for nausea, 23% vs. 19% for vomiting).

Check out our full analysis of this announcement and its impact on the next-gen glucagon landscape below:

Comparison to Competitors

• With data now in-hand, management once again underscored faster onset with dasiglucagon compared to Xeris’ Glucagon Rescue Pen and Lilly’s nasal glucagon as integral to HypoPal gaining commercial traction. Most importantly, this would presumably lead to better outcomes for patients in emergency situations. From a commercial standpoint, faster onset would differentiate dasiglucagon from its competitors, both of which are ahead of Zealand in the regulatory timeline. Indeed, management believes they have a leg up on the competition in this arena, emphasizing that dasiglucagon demonstrated 99% hypoglycemia rescue 15 minutes after injection, whereas competitors have only released data at the 30-minute time-point. This said, Dr. Steensberg did acknowledge the difficulties of comparing data across these studies as they are all incredibly different (see table below). On this point, he believes a bias against dasiglucagon exists since both Xeris and Lilly defined time to plasma glucose recovery as the first increase in plasma glucose of ≥20 mg/dL (Zealand’s definition) or plasma glucose ≥70 mg/dL, a purportedly easier goal to achieve. Could head-to-head studies be on the horizon? We certainly hope so. Until then, here’s a collection of the most recent onset and efficacy data from all three candidates:

• HypoPal Rescue Pen remains set for a 2H19 NDA filing, following 1H19 completion of a pediatric study for dasiglucagon (n=40 children down to the age of six). Both Xeris (Glucagon Rescue Pen) and Lilly (nasal glucagon) filed NDAs in 2Q18 (Lilly also filed an MAA with EMA), meaning that Zealand is about 1-1.5 years behind in the regulatory pathway. When asked about this in Q&A, CEO Ms. Britt Meelby Jensen commented that “speed [of filing] is certainly important.” Dr. Steenberg also reminded listeners of market research that Zealand has conducted, suggesting that patients prefer an easy-to-use pen over a nasal spray (Lilly) for glucagon.

Commercialization and Market Potential

• Ms. Jensen valued the current US glucagon market at $350 million, projecting it could exceed $1 billion by 2030 as easier-to-use, next-gen glucagon candidates gain traction and raise awareness. Zealand maintained their market prediction for 2025 at $700 million, representing a doubling of the market in the next seven years. While some may see this growth as quite ambitious, it pales in comparison to Xeris’ estimate, which placed the US glucagon market potential at $2 billion.  To be sure, market penetration could be greatly improved, and new, patient-friendly products should help get glucagon into far more patient hands; our sense is that many patients and families do not widely embrace or consider glucagon as useful or necessary, but a more convenient product could really shift that thinking. As such, innovative glucagon products certainly stand to expand the current market. We would love to see Zealand and other manufacturers leverage these products in campaigns to both improve glucagon prescribing practice and promote uptake within the diabetes community.

  • Interestingly, Zealand predicted the bulk of volume growth to come from outside of the US and EU top 5. According to the figure below, the rest of the world currently comprises about 20% of global glucagon prescriptions – expected to greater than double to ~44% by 2030.

• Zealand reiterated their intent to partner for dasiglucagon commercialization. Ms. Jensen and Dr. Steenberg elaborated on this in Q&A, stating that Zealand is open to both global and regional partnerships. Moreover, the company intends to manufacture at least the active pharmaceutical ingredient (API) themselves, as they plan to commercialize dasiglucagon for congenital hyperinsulinism (CHI) and pump-use without a partner.

Future Research and Development

Zealand plans to market dasiglucagon for (i) emergency hypoglycemia rescue; (ii) congenital hyperinsulinism via chronic infusion; and (iii) bi-hormonal pump-use. Together, this requires a lot of trials. Here is an overview of all ongoing trials for dasiglucagon for which we have yet to receive full results:

• Management identified faster onset compared to other next-gen glucagon candidates as key to HypoPal gaining commercial traction. To this end, Zealand reviewed positive results from a phase 2aPK/PD study presented at ADA 2018 earlier this summer, in which normoglycemia (>70 mg/dl) was restored in a median time of 14, 10, 6, and 6 minutes for respective dasiglucagon doses of 0.03 mg, 0.08 mg, 0.2 mg, and 0.6 mg. For comparison, Xeris also provided PK/PD data for their Glucagon Rescue Pen at ADA, although using a different metric. Mean time to resolution of autonomic symptoms was 15 minutes with Xeris’ autoinjector vs. 14 minutes with Lilly’s glucagon reconstitution kit (p>0.05); mean time to resolution of neuroglycopenic symptoms was 16 minutes vs. 14 minutes (p>0.05). We’ll be curious to see how Zealand approaches the concept of superiority vs. Lilly’s and Xeris’ products – are head-to-head studies on the horizon? We hope the manufacturers focus on expanding the class once their compounds are available.

Questions and Answers

Q: About how long does it take for reconstitution of the competing product?

Dr. Steensberg: It of course heavily depends on if it is an HCP or family or friend doing the reconstitution. In human factors studies we have seen around 85% of people don’t even manage to give the appropriate dose with the old kits. For an HCP it will take several minutes just to follow the instructions. It’s a fact that most people in an emergency situation will not know how to inject.

Q: How will the pediatric trial be different from the adult trial?

Dr. Steensberg: It will be a study down to the age of six, and we will test only one dose of dasiglucagon. In our eyes, we have to be particularly careful with very small children, but we are comfortable with the design. It will be similar to the adult phase 3 study.

Q: Can you comment on some of the other secondary endpoints? Will you be presenting them at a future conference?

Dr. Steensberg: Yes, we will be sharing them. For simplicity, you can say that at 15 minutes we had 99% of patients recovered. That speaks for itself. At an earlier time point, say 10 minutes, of course it was less. Keep in mind that the median recovery was 10 minutes. We will present these data, but I can only say right now that it is in line with what you would expect. I would like to highlight that we have defined rescue as an increase in fasting plasma glucose of 20 mg/dL. Others use an increase of 20 mg/dL or plasma glucose above 70 mg/dL, which is actually easier to achieve. So we believe, if you compare across trials, that there is a bias against our data here.

Q: What is needed in terms of the regulatory requirements for the HypoPal?

Dr. Steensberg: We will also do the pediatric study in 40 children down to the age of six. We will also do a smaller, phase 3 trial with the autoinjector to confirm the efficacy of the injector which will be initiated shortly as well. We also have the ongoing classical regulatory steps to confirm the stability, etc. These trials will take us to 2H19 when we will submit the NDA.

Q: What are your high-level thoughts on commercialization strategy?

Ms. Jensen: A couple years ago we decided to take dasiglucagon through registration ourselves because it was straightforward in terms of clinical development and we didn’t want to lose time. Secondly, we felt the cost of clinical development was manageable for a company like ours. However, we are looking for a commercialization partner for the dasiglucagon HypoPal to ensure that it will be widely available and expand the number of patients that use it. How we are thinking about this is that we are waiting for the right time to close a deal with a partner. This is dependent on two things: value maximizing and making sure we engage with the best possible partner at the time of launch. We are in discussions with different companies and have a pretty good idea of how the partnership will be done. With some of our other products, for example, the CHI program, that is much more possible for a company like ourselves to commercialize – the target market is narrower and more well-defined. That is where we aim to market ourselves with a key focus on the US.

Q: Have the key competitors not released data for the 15-minute time window, and does dasiglucagon compare favorably within the 30-minute time window that the competitors have released?

Dr. Steensberg: There have not been a lot of data released by the key competitors. The phase 3 trials for both Xeris’ and Lilly’s products do have patients within 30 minutes who have not recovered according to those studies’ definitions. I think if you look into the means of our data as well they in general faster than what we have otherwise seen, but I would also have to highlight that it is difficult to compare across studies.

Q: How much does the infant/adolescent market represent of the existing market?

Ms. Jensen: We expect that around 40%-45% of the currently prescribed rescue kits are to children.

Q: Could you elaborate on the competitors’ timelines?

Ms. Jensen: Lilly has recently filed an NDA for its nasal glucagon in both the US and Europe. Xeris filed in August in the US only. We also know that Lilly has a glucagon in phase 1 that we have not heard about in 2-3 years, and Novo Nordisk announced a glucagon candidate in February.

Q: Which will come first, the partner or the filing?

Ms. Jensen: We will plan to file ourselves as we believe this to be the fastest way to market. Given that there are two competitors ahead of us, speed is certainly important. For a product of this type we don’t see a big challenge in terms of who manages the regulatory filing. Since we are looking for a commercialization partner it is not particularly important whether we engage with that partner before or after regulation. We want to make sure that our partner is fully committed to this product by the time of launch to maximize revenue.

Dr. Steensberg: I think it’s also important to note that the HypoPal Rescue Pen is just one product offering containing dasiglucagon. As we are also developing dasiglucagon as a chronic infusion for CHI and for use in dual-hormone pumps we will have multiple product presentations for FDA, so it makes a lot of sense for us to take the lead here.

Q: In terms of partnership, are you looking for a global partner, global launch? Or will you target the US first?

Ms. Jensen: I think we are flexible. Our number one market priority is the US as it is the biggest and highest value market today. We are also open to one global partner or regional partners. What’s important to us is maximizing value and finding partners that will push the product in relevant markets.

Q: If you opt for regional partnerships, how might manufacturing and cost of goods sold be split?

Dr. Steensberg: Zealand is building a fully capable organization including product supply as we will also commercialize our own products within rare diseases. We are building an organization that can support the rescue pen on the market. We could clearly see a situation in which we are in part responsible for the supply chain until there is a label, at which point the partner will be responsible for distribution. If we had multiple partnerships that will be the logical choice to drive down costs with larger volumes. As a minimum we will likely produce the API because that goes into our products for CHI and dual-hormone pumps.

--by Peter Rentzepis, Ann Carracher, and Kelly Close