Symlin (pramlintide) has long been the unfavourable adjunct therapeutic for type 1 diabetes (T1D) in the US. First launched by AstraZeneca in 2005, pramlintide is an injectable formulation human amylin that has been shown to reduce HbA1c and body weight when taken with insulin. Pramlintide is not, however, very popular among T1D patients and there are some serious limitations to the use of the drug due to increased rates of hypoglycaemia. Hypoglycaemia and glycaemic control are two of the largest unmet needs in the T1D space. As both amylin and insulin are secreted together in the body, coformulations of the two may address these unmet needs that remain with insulin-only treatments.

Symlin’s patent expired in 2019 and while its role as an adjunct was disappointing to both patients and key opinion leaders (KOLs) alike, its potential for coformulation with insulin is showing promise. Amylin is a peptide hormone that is co-secreted with insulin from the pancreatic b-cells and is thus deficient in diabetic patients.

Three companies are looking into coformulation with pramlintide, namely Adocia, Xeris and Arecor. AstraZeneca was previously investigating the coformulation of pramlintide with a human insulin, but it has since discontinued its research in the space. Adocia’s insulin co-formulation pipeline is the most robust, with three different coformulations in development. At this year’s American Diabetes Association (ADA) Annual Meeting, data from part two of the Phase Ib trial of M1Pram (ADO09, human insulin + pramlintide) demonstrated an average of 58 minutes more time in range between 70mg/dL and 170mg/dL, and 63 minutes more time in range between 80mg/dL and 140mg/dL compared to Novo Nordisk’s Novolog (insulin aspart).

Novolog has demonstrated a significant benefit over human insulin since its launch in 2000 and is the market leader in prandial or mealtime insulin alongside Eli Lilly’s Humalog (insulin lispro). Those taking M1Pram required 12 fewer units of prandial insulin a day compared with insulin aspart and reported a decreased appetite, thus experiencing a mean 1.6kg reduction in body weight over 24 days, whereas participants taking Novolog gained a mean 0.4kg of body weight. These results demonstrate the benefit of the combination of both hormones in addressing postprandial changes in blood glucose, which is difficult to manage with any of the currently marketed insulins alone. Adocia is currently studying M1Pram in a Phase II study to compare M1Pram with Humalog, with results expected in the second quarter of next year.

In addition to M1Pram, on 29 June, Adocia announced it had dosed its first patient in a Phase I trial investigating BioChaperone LisPram (insulin lispro + pramlintide) for insulin pump delivery in comparison with Humalog. A coformulation of insulin aspart and pramlintide is also in early development. At this year’s Endocrine Society Annual Meeting (ENDO), Xeris presented results from its Phase II study of XP-3924 (human insulin + pramlintide) and reported comparable postprandial glycaemic control to that observed with co-administered regular insulin plus pramlintide, as well as a 63% decrease of hyperglycaemia when compared to regular insulin.

While these results are promising, Xeris will need to use an insulin analogue as the active comparator to demonstrate a benefit, as human insulins are no longer actively prescribed. Time-in-range will also be a critical endpoint to include as more patients adopt continuous glucose monitoring. Arecor’s AT299 (insulin + pramlintide) coformulation is still preclinical.

Innovation in the insulin space has been relatively consistent over the last 20 years, as human insulins were replaced by insulin analogues, and the second-generation insulin analogues are now becoming established in the market. Despite these launches of novel insulins, the relative impact of these insulins on a patient’s quality of life is not significant enough to warrant the premium pricing in some cases.

Achieving glycaemic control and managing hypoglycaemia is still a major issue in T1D. GlobalData has found that more than 90% of T1D patients in the US still experience recorded hypoglycaemia, with more than 27% experiencing severe hypoglycaemic events, 54% experiencing nocturnal hypoglycaemia, and more than 21% with hypoglycaemia unawareness. Of all T1D patients worldwide, 47% are overweight or obese and only 20–30% meet their glycaemic targets. Insulin pumps and continuous glucose monitors are helping to an extent, but many patients still require additional help.

Some KOLs have expressed pushback against the use of pramlintide due to their experiences prescribing the original formulation and the increased hypoglycaemia and gastrointestinal symptoms. Others have, however, pointed out that these novel formulations have different pharmacokinetics and that coformulation seems to provide greater benefits and no hypoglycaemia, despite the persistence of some gastrointestinal symptoms.

Amylin inhibits glucagon secretion, delays gastric emptying and acts as a satiety agent in addition to its impact on blood glucose. With some interviewed KOLs calling pramlintide the ‘new glucagon’, there is great potential for these therapies as they reduce the number of required therapeutics, injections and units of insulin a day, all of which make the daily management of T1D easier on the patient. While coformulations are still early in development, GlobalData expects that coformulations, particularly in combination with insulin pumps and continuous glucose monitors, could disrupt the current insulin standards.