Zealand R&D Day highlights impressive portfolio of peptide candidates across spectrum of metabolic diseases – March 4, 2021

Zealand held its 2021 “R&D Day” on a virtual platform on Thursday, with Live Q&A with management on Friday (we expanded this report). See the video presentations and slide decks here; we loved the live Q&A that happened early this morning – see later in the report. 

Pipeline Overview and Peptide Platform

Zealand currently boasts 12 drug candidates across metabolic and GI/inflammation therapeutic areas. All of these therapies are being developed through Zealand’s innovative peptide discovery platform, which utilizes computational chemistry and other technologies to enhance stability, bioavailability, and modify characteristics of a candidate to improve safety and efficacy. Head of Discovery and Innovation Dr. Rie Schultz Hansen cited Zealand’s dasiglucagon as a prime example of this technology at work: by swapping out seven of 29 amino acids in glucagon’s native sequence, the company created a novel candidate that increases blood sugar (glucagon’s normal function) without aggregating in solution (a common problem associated with glucagon use). This platform has also been used to design peptide candidates with dual pharmacology, like Zealand’s GLP-1/GLP-2 dual agonist dapiglutide being explored in short bowel syndrome.

Update on Partnership with Beta Bionics: Year-long Phase 3 Bi-hormonal Bionic Pancreas Pivotal Slated to Begin in 2H21

Almost half of the thirty-minute metabolic portfolio update focused on Zealand’s partnership with Beta Bionics to test and launch Beta Bionics’ bi-hormonal bionic pancreas with Zealand’s dasiglucagon. Zealand Head of Medical Affairs Dr. Danilo Verge and Harvard Medical’s highly respected Dr. Steven Russell reviewed phase 2/pre-pivotal results and presented the structure for an upcoming phase 3 trial investigating dasiglucagon in the dual hormone iLet bionic pancreas (to skip to this discussion go to minute 14:00 here).

Following positive pre-pivotal results that were first announced in June 2019 and presented at FFL 2020 last July and a “very productive” end of phase 2 meeting with the FDA, the twelve-month pivotal trial for the bi-hormonal iLet system with dasiglucagon is set to begin in 2H21. This is slightly behind schedule based on the timeline offered at FFL 2020 that slated the pivotal for “early 2021” with a launch “in 2022, maybe early 2023.” As a reminder, the trial is considerably longer than insulin pump pivotals have generally been in the past (six months for Control-IQ and three months for MiniMed 780G), primarily because Zealand’s liquid-stable glucagon analog dasiglucagon has never been used long-term with type 1s.

Based on today’s presentation, the trial will investigate three interventions – bihormonal iLet with Dasiglucagon (BHBP), insulin-only iLet (IOBP), and “usual care” – in both pediatric (n~350) and adult (n~350) populations with type 1 diabetes. The primary endpoint will measure the superiority of A1c reduction with BHBP vs. IOBP at 26 weeks, and key secondary endpoints will investigate long-term safety/efficacy over 52 weeks and non-inferiority for time in hypoglycemia.

Members of our team (Kelly) have used the iLet pump in a trial before and spoke very encouragingly about its size and ease of use, key positives not only for people with diabetes but also increasingly for HCPs who are very short on time and who also need easier to train devices given that most training is done remotely currently and presumably in the future.

• In Q&A on Friday, we heard more about the study design for the pivotal phase 3 study. Dr. Steensberg expressed optimism about enrolling patients quickly. This conviction was made on the basis of Beta Bionics’ pivotal insulin-only trial for the bihormonal bionic pancreas, which showed a rapid enrollment period even in the face of setbacks brought on by the pandemic. Moreover, it is possible that some patients from the insulin-only trial could be enrolled in the upcoming bihormonal trial. Zealand also expects high interest in the trial given the device’s fully automated nature, which may reduce the burden of compliance for type 1 patients. Drs. Steensberg and Verge also discussed the trial’s primary endpoint, which will assess A1c superiority of the bihormonal device versus the insulin-only device at 26-weeks. In the phase 2 study, 90% of patients using the bihormonal pump achieved an equivalent A1c of <7%, while only 50% of patients achieved <7% A1c in the insulin-only group.
• Some other interesting references to the biohormonal iLet device also came up during Q&A on Friday. As has been known since Dr. Ed Damiano shared this at multiple meetings over time with patients, particularly its Friends for Life updates last July, the device takes into account the patient’s weight as its primary input. Where not as much has been shared is about the machine learning algorithms that are used to determine the amount of dasiglucagon and/or insulin to be delivered at a given time. This will vary, of course, by weight and by glycemic management, where the current glucose is, how fast it is moving, etc. During the Q&A, Dr. Steensberg mused that in “real life” use, each patient would presumably require one dasiglucagon cartridge per week. This was quite fascinating also – we would assume there would be a fair degree of variability on this as well depending on how much someone eats, how variable the glucose, how much they are exercising, etc. No details on pricing have been given, particularly on glucagon, and it will be very interesting to see where this conversation advances.
  

Dasiglucagon Updates: Impending HypoPal Rescue Pen Launch in US, Phase 2 and 3 Studies in Hypoglycemia Ongoing

As announced in Zealand’s 3Q20 update, the dasiglucagon HypoPal rescue pen is aiming for a potential commercial launch in the US following its March 27^th FDA PDUFA date. Zealand today announced it is planning for the HypoPal’s successful launch, which includes a focus on expanding US capabilities – as a reminder, Zealand hired Mr. Frank Sanders as the President of Zealand Pharma US in June 2020, launched headquarters in Boston in July 2020, and created a new Global Medical Affairs division in September 2020 with Drs. Danilo Verge and David Kendall at the helm.

Elsewhere in the company’s dasiglucagon program, Zealand today gave an update on its phase 2 and 3 trials exploring the therapy in various hypoglycemia indications. Firstly, Zealand has an extensive phase 3 program for dasiglucagon in congenital hyperinsulinism (CHI): one of these trials has completed with positive results, another set to complete in 2H21, and an open-label extension study which is still recruiting. The company also has plans to complete “mini-dose” trials in post-bariatric surgery (phase 2b outpatient study to begin 1H21) and in exercise-induced hypoglycemia in type 1 (also planned for 1H21). Exercise-induced hypoglycemia is a very big deal and something that hasn’t yet been “cracked” in the closed loop – from our view, the second opportunity is far bigger than the first, but both are critical.

Three Phase 2 Trials for BI-partnered GLP-1/Glucagon Agonist in Obesity and Other Metabolic Diseases; Novel Obesity Candidates Approaching Phase 1

Select updates were given on Zealand/BI’s dual GLP/glucagon agonist BI456906. The companies are currently pursuing three phase 2 trials: (i) one currently recruiting in type 2 diabetes, set to complete in 3Q21 (n=350); (ii) one not yet recruiting in obesity, set to complete in 3Q22 (n=350); and (iii) one not yet recruiting in NASH, set to complete 1Q23 (n=240). On the basis of positive preclinical results, Zealand is also anticipating the start of phase 1 obesity trial in 2021 for its amylin analog (ZP8396) alone and in combination with other peptides (e.g., GLP-1, GIP), akin to Novo Nordisk’s semaglutide/amylin combination in obesity and Lilly’s dual agonist for T2D. The company is also pursuing IND enabling toxicology studies for its GIP agonist (ZP6590), which also allows for potential co-administration with other peptides.

Major Takeaways from Live Q&A

Zealand today held a follow-up Live Q&A session on its R&D presentation with investors – see here for an audio replay of the entire conversation. Zealand’s Dr. Emmanuel Dulac, Dr. Adam Steensberg, Dr. Danilo Verge, and Dr. Rie Schultz Hansen were all on the call to give more insight into their presentations released yesterday.

• Regarding Zealand’s obesity and metabolic disease pipeline, management today discussed a number of compounds during Live Q&A. We will be updating this as time permits but for now would encourage all those interested in the “next-gen” GLP-1, amylin, GIP, and other peptides to listen directly.
  

• For example, management expressed confidence that its pre-clinical once-weekly amylin and GIP analogs could be differentiated from similar products in development. Management emphasized that unlike other competitors being developed (like Novo Nordisk’s long acting amylin candidate), Zealand’s peptides have the potential to be co-formulated with nearly any other peptide molecule. This characteristic opens up opportunities for partnerships in the future – such as Zealand’s amylin with another company’s GLP-1 receptor agonist, for example. This may interest a company like AstraZeneca, for example, which de-emphasized GLP-1 when it had fewer resources; it’s speculative on our part, but presumably if they could differentiate Bydureon or some advanced-level compound and get back into GLP-1, that could be of interest – purely speculative of course. Management expressed its ambition to bring its amylin peptide to phase 1 sometime this year, and to bring its GIP peptide to phase 1 next year.

• There were some very interesting perspectives shared on the Boehringer compounds in development on which they are partnered – these were high level but fascinating.

There’s much more to take in regarding management Q&A – it’ll be up for a “for more days,” management said.

--by Joseph Bell, Katie Mahoney, Rhea Teng, and Kelly Close