One Peptide, Two Receptors Lilly and KeyBioscience's Long-Acting Answer to Diabetes and Obesity

This application claims a single 32 residue peptide that switches on both the amylin receptor and the calcitonin receptor, chemically rebuilt so that it survives long enough in the body to be dosed infrequently. The applicants are Eli Lilly and Company of Indianapolis and KeyBioscience SA of Stans, Switzerland, the two partners behind a dual agonist programme aimed at type 2 diabetes, obesity, dyslipidaemia and fatty liver disease.

The Problem

The specification opens with two hormones that each do a useful job badly. Amylin is a peptide hormone co-secreted with insulin from the pancreatic beta cells and is deficient in people with diabetes. It suppresses glucagon, slows gastric emptying and acts as a satiety signal. An amylin analogue, pramlintide, is already available for insulin-using diabetic patients, but its elimination half-life is under an hour, so it has to be injected at every meal.

Calcitonin, made in the thyroid, regulates blood calcium and phosphate. Salmon calcitonin is available for conditions such as hypercalcaemia, and it has the same failing: a half-life of less than two hours, and dosing once or several times a day.

Compounds that agonise both receptors at once have already been shown to lower blood glucose and induce weight loss, and the specification cites three earlier published applications to that effect. The obstacle is durability. The natural half-life of the known dual agonists is short, and the modifications tried so far to extend the time of action have cost potency. These molecules are also awkward to formulate: they tend to fibrillate, and they carry a disulfide bond that is labile at neutral pH.

What This Invention Does

The disclosure names a specific molecule. Compound I has the sequence Acetyl-ASHLSTAVLGKLS-Aib-ELHKLEDYPRTDVGAESP-NH2, given as SEQ ID NO:1. Two design decisions are visible in that string alone. There is no cysteine anywhere in it, which means the labile disulfide bond present in both human calcitonin and human amylin has simply been engineered out. And position 14 is Aib, a non-natural residue used to stiffen a helix and blunt enzymatic attack. The N-terminus is acetylated and the C-terminus is a primary amide, both of which shield the ends of the chain from exopeptidases.

Claim 1 is narrower still. It covers Compound II, which is Compound I acylated at the epsilon amino group on the lysine side chain, through a short ethylene glycol spacer and a gamma-glutamate linker, to a long chain fatty diacid. That acylation strategy is the standard route to a long-acting peptide: the fatty chain binds reversibly to circulating serum albumin, which parks the drug in the bloodstream and slows its clearance. Claim 2 is the same molecule written as a closed definition.

The description also lists other half-life extension options that could be bolted onto SEQ ID NO:1: an immunoglobulin Fc portion or fragments of it, human serum albumin, a VHH nanobody, a monoacid or diacid, and a polyethylene glycol moiety or an alternative such as polysarcosine.

From claim 3 onward the application turns to use, with method claims for treating type 2 diabetes, obesity, dyslipidaemia and non-alcoholic steatohepatitis, and for lowering food intake, body weight, glucose and triglycerides. Composition and use claims follow, along with a claim to administering the composition in combination with an incretin or incretin analogue, a point the sequence listing supports with GLP-1 and GIP style comparators including dulaglutide.

Key Features

• A single peptide with two targets. One molecule agonises both the amylin and the calcitonin receptor, rather than combining two separate drugs.
• The disulfide bond designed out. Neither Compound I nor Compound II contains a cysteine, removing the bond the specification identifies as labile at neutral pH.
• A non-natural residue at position 14. Aib replaces a standard amino acid to stabilise the peptide against degradation, with the N-terminus acetylated and the C-terminus amidated.
• Fatty diacid acylation for staying power. Claim 1 is directed to the version acylated on a lysine side chain through a glycol spacer and gamma-glutamate, the albumin binding approach used to turn short-lived peptides into infrequently dosed ones.
• A broad menu of alternative extenders. Fc fragments, human serum albumin, VHH nanobodies, PEG and polysarcosine are all disclosed as substitutes for the fatty acid.
• Claimed for combination with incretins. Separate claims cover dosing the composition alongside an incretin or incretin analogue, which is where the current obesity market sits.

Who Is Behind It

Eli Lilly and Company needs little introduction as a metabolic disease developer. Its partner, KeyBioscience, is a small Swiss company built around what it calls the DACRA platform, short for dual amylin and calcitonin receptor agonists, with candidates including KBP-042, KBP-089 and KBP-336. Lilly announced a strategic collaboration with KeyBioscience in 2017, taking worldwide development and commercialisation rights, and the two extended that arrangement in 2024.

Five inventors are named: Tamer Coskun and Hongchang Qu on the Lilly side, and Morten Asser Karsdal, Kim Vietz Andreassen and Kim Henriksen on the KeyBioscience side, the last three being the Danish peptide and bone biology group from which the DACRA work grew.

The priority chain is a long one. This is a divisional of Australian application 2024219572, which was filed on 10 September 2024. The earliest priority is United States provisional application 63/127,186, filed on 18 December 2020, taken forward through international application PCT/US2021/063990 filed on 17 December 2021.

Why It Matters

The obesity and metabolic drug market has spent several years dominated by GLP-1 receptor agonists, and the field’s attention has moved to what comes next. Amylin analogues are the most watched of those candidates, because they act on satiety through a different pathway and appear to combine well with the incretins rather than competing with them. Adding calcitonin receptor agonism to the same molecule is the distinguishing bet here, on the argument that it brings insulin sensitisation along with the appetite effect.

The chemistry in this document is not exotic. Acetylate one end, amidate the other, drop in an Aib, remove the disulfide and hang a fatty diacid off a lysine through a spacer: that is the modern toolkit for converting a fragile natural hormone into an injectable that lasts. What is interesting is how narrow the claim is. Claim 1 does not cover a family or a formula with variable positions, it covers one named compound and its salts. A divisional that comes down to a single sequence usually signals a specific candidate that has survived selection and is worth fencing individually, and the filing pattern says the same thing: a December 2020 priority date carried through a PCT, an Australian entry and at least two divisional generations to a March 2026 filing is a family kept deliberately open while the programme progresses.

Related Concepts

• Amylin – the pancreatic hormone whose receptor is one of the two targets.
• Calcitonin – the thyroid hormone whose receptor is the other.
• Pramlintide – the existing amylin analogue whose short half-life the specification uses as its starting problem.
• Cagrilintide – a rival long-acting amylin analogue showing where the field is heading.
• Serum albumin – the blood protein the acylated fatty chain binds to in order to extend circulation time.
• Amyloid – the fibrillation behaviour that makes amylin and calcitonin analogues difficult to formulate.

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AU 2026202104 was published in the Australian Official Journal of Patents on 9 April 2026 and is open for public inspection. Patent applications represent inventions that are sought to be protected and do not necessarily reflect commercially available products.