Multi-hormonal approach for diabetes management
In healthy people normoglycaemia is maintained by a time-dependent hormonal pattern. This pattern is mainly comprised of four hormones: insulin, glucagon, glucagon-like peptide 1 (GLP-1) and amylin. In patients with T1D this hormonal pattern is severely disrupted.
Exhibit 7: Representation of hormonal pattern
BC Glucagon to the rescue
Adocia has applied its BC technology to generate a new formulation of human glucagon. The company is developing BC Glucagon as a potential improved product of current rescue treatment for severe hypoglycaemia. Potential additional indications would be: 1) as a dual hormone artificial pancreas, which would secrete insulin and glucagon and would be an improvement over hybrid closed-loop insulin pumps as glucagon would allow more use of insulin by reducing hypoglycaemia at night and during the day; 2) for the treatment of congenital hyperinsulinism, an orphan disease that affects 1 in 50,000 children worldwide; and 3) for the treatment of chronic hypoglycaemia resulting from post-bariatric surgery, as around 0.2% of bariatric surgery patients suffer from chronic hypoglycaemia. The company intends to advance it into late-stage development; the timeline has not been released.
Adocia has conducted a Phase I clinical trial (NCT03176524) in 27 patients comparing two formulations of BC Glucagon to Novo Nordisk’s Glucagen Hypokit. The median time to reach a clinically safe blood glucose level was 11 minutes for BC Glucagon and c 7 min for Glucagen. All subjects achieved resolution of hypoglycaemia at 35 minutes (press release). Given the importance that time has in this emergency setting, we believe BC Glucagon will need to show it is a ready-to-use solution with a similar profile to current glucagon to gain market share. Full data will be released at a major diabetes congress in late 2018.
Current glucagon rescue kits on the market are Novo Nordisk’s GlucaGen HypoKit (sales not disclosed) and Eli Lilly’s Glucagon emergency kit (2017 sales $142.2m). However, due to glucagon’s instability in aqueous solutions, it must be kept lyophilised and needs to be mixed with sterile water before use. In this emergency situation most caregivers have difficulties administering the right dose to the patient. We view BC Glucagon as an interesting ready-to-inject alternative. Current competitors are Xeris Pharmaceuticals (expects to file an NDA with the FDA in Q218); Zealand Pharma’s dasiglucagon (Phase III, data expected in 2018); and Arecor (preclinical). Eli Lilly’s Locemia is developing a nasal spray of glucagon for the same indication; an NDA submission is expected in 2018. According to Adocia, the current market for these devices is $300m in the US based on similar sales for Lilly and Novo Nordisk’s products, which it expects to grow due to other ready-to-use kits entering the market.
BC Pram Insulin, a combination of amylin analogue and insulin
Adocia is developing BC Pramlintide Insulin (BC Pram Insulin) as a combination product of pramlintide and human fast-acting insulin for diabetic patients. The company started a first-in-man clinical trial in April 2018. Amylin is a hormone that is co-secreted with insulin in physiologic conditions. Amylin acts synergistically with insulin by suppressing glucagon secretion, slowing down gastric emptying and creating a feeling of satiety. Pramlintide (Symlin, AstraZeneca) is an analog of amylin that has demonstrated better glycaemic control, reduced insulin consumption and reduced weight gain in clinical trials when used in addition to prandial insulin compared to prandial insulin alone. Symlin is approved by the FDA to control blood sugar levels in adults with T1D or T2D. Patients have to undergo seven injections per day: one of basal insulin, three of prandial insulin and three of Symlin. According to Adocia, by combining pramlintide and insulin in a single product, BC Pram Insulin could significantly improve post-prandial control in people with diabetes without increasing the number of daily injections. AstraZeneca reported FY17 sales of $48m for Symlin. EP consensus forecast is $63m in 2022.
BC Glucagon GLP-1 for obesity
Another opportunity for the BC technology is in obesity. Adocia is using the GLP-1 receptor agonist exenatide (Byetta, AstraZeneca, 2017 sales $176m, off-patent) in combination with glucagon. Adocia plans to start a first-in-man study in Q418.
Although obesity is a potential large market (36.5% of US adults were obese in 2014 according to the Centers for Disease Control), a number of companies (eg Arena, Vivus and Orexigen) targeting this market failed to achieve meaningful sales; among other reasons, due to increased side effects, small weight loss and reluctance from physicians to prescribe drugs to treat obesity. On the other hand, GLP-1 receptor agonist liraglutide (Saxenda, Novo Nordisk) has been successful, with 2017 sales of $389m and is projected to achieve $927m in 2022 according to EvaluatePharma’s consensus forecast.
We believe that a product with dual GLP-1 and glucagon agonistic properties could be effective in promoting weight loss, increasing energy expenditure and reducing calorie intake. For example, this clinical study shows that glucagon and GLP-1 co-infusion significantly reduced food intake by 13% in the study meal compared with placebo, which was also significant with respect to the administration of either glucagon or GLP-1 alone.
BC GLP-2 for short bowel syndrome
The BC technology is used to stabilise GLP-2 analog teduglutide (Gattex, Shire, 2017 revenues $336m, EP consensus forecast for 2022 is $505m) in a ready-to-use liquid formulation for short bowel syndrome (SBS). Gattex needs reconstitution prior to use, which involves 22 steps, two syringes, is time consuming and there is the potential of dosing mistakes. Adocia plans to start a first-in-man study in Q418.
SBS is a malabsorption disorder associated with partial or total loss of intestinal function. It usually develops after surgery. The worldwide incidence is estimated at two to five patients per million people (ref). Management of SBS frequently requires lifelong parenteral nutrition. GLP-2 stimulates the growth of intestinal tissue, increases nutrient absorption potentially reducing dependence on parental nutrition.
Glepaglutide from Zealand Pharma is a ready-to-use formulation of a new GLP-2 agonist analog that will start a Phase III trial in 2018 as a once- and twice-weekly dose. Positive Phase II results were announced in June 2017. Evaluate Pharma’s forecast is for launch in 2020 and revenues of $125m in 2022. We believe that BC GLP-2 will need to differentiate itself in terms of dosage, or a broader application beyond patients on parenteral nutrition to compete with glepaglutide.