In the hunt for the next 'GLP-1', amylin therapeutics, which have shown strong weight-loss results in clinical trials, have become a major focus for both multinational pharma and the scientific community.

Amylin, also known as islet amyloid polypeptide (IAPP), is a member of the calcitonin peptide family, which also includes calcitonin, α-calcitonin gene-related peptide (α-CGRP), β-calcitonin gene-related peptide (β-CGRP), adrenomedullin, and adrenomedullin 2. These peptides play an important role in energy metabolism.

Amylin is a 37-amino acid peptide (Figure 1) expressed primarily by pancreatic islet β-cells and co-secreted with insulin. Amylin expression has also been reported in other locations like brain and gut^[1].

Amylin is secreted by the pancreas in response to nutrient intake or secretagogue stimulation. Food intake increases amylin release and circulating levels, which could have effects on multiple organs, including the heart, skeletal muscle, liver, intestine, and brain. Amylin signals through amylin receptors (CTR–RAMP complexes) and primarly acts on circumventricular organs of the brain, where it suppresses appetite, delays gastric emptying, enhances satiety, and reduces food intake (Figure 2)^[1]. Thus, amylin contributes to the regulation of glucose homeostasis and energy metabolism.

Upon secretion from the pancreas (blue arrow), circulating amylin reaches a broad range of organs and tissues, with primary actions localized to the circumventricular regions of the brain. Amylin activity is indicated by red (direct) and pink (indirect) arrows.

Amylin functions as a key regulator of glucose homeostasis while exhibiting intrinsic anorectic and weight-reducing properties, thereby providing a compelling therapeutic basis for obesity. However, native human amylin is limited by a short circulating half-life (~30 min) and a strong propensity for toxic oligomerization, precluding direct clinical use. These constraints necessitate the development of engineered amylin analogs with enhanced stability, reduced aggregation, and extended pharmacokinetics.

Pramlintide is the first—and, as of 2026, the only—approved amylin drugs. Pramlintide is engineered as a non-aggregating chimeric peptide, it incorporates three proline substitutions from rat amylin into the human sequence (Figure 3), thereby preserving amylin-like pharmacology across the calcitonin receptor and AMY receptor subtypes (AMYR1-3)^[1-3].

Approved by the FDA in 2005 as an adjunct to insulin in T1DM and insulin-treated T2DM, pramlintide has demonstrated consistent weight-reducing effects in both diabetic and obese populations. However, its clinical advancement in obesity has been constrained by frequent dosing (2-3 daily injections) and relatively high manufacturing costs^[1-3].

Pramlintide has been approved by FDA in 2005 as an adjunct therapy to insulin in T1DM and T2DM. Pramlintide has also been demonstrated weight-reducing effect in both diabetic and obese patients in clinical trials. However, its clinical advancement in obesity has been constrained by frequent dosing (2-3 daily injections) and relatively high manufacturing costs^[1,3].

Petrelintide, eloralintide, and cagrilintide are long-acting amylin analogues engineered via multiple amino acid substitutions on the pramlintide/amylin scaffold and long-chain fatty acid modification (Figure 4). These modifications enable extended half-time, enhanced stability and prevent the formation of toxic oligomers, thus allow once-weekly subcutaneous dosing.

Eloralintide is a selective AMYR agonist under clinical investigation. Compared with other amylin analogs, eloralintide exhibits reduced affinity for the CTR and increased selectivity for AMYR^[5]. In phase II, a 48-week trial showed high dose eloralintide achieved a mean -20.1% weight reduction for overweight adults without T2D, demonstrating superior weight loss compared to placebo^[6].

Cagrilintide is one of the fastest progressing long-acting amylin drugs in clinical development. It has achieved significant results in multiple phase III clinical trials, particularly showing a 15.6% reduction in body weight after 32 weeks of combination therapy with semaglutide^[7].

Amycretin is a unimolecular dual agonist of AMYR and GLP-1R, consisting of 68 amino acids. It is formed by linking the GLP-1R agonist moiety and the AMYR agonist moiety via a linker peptide (GGGGE). The GLP-1R agonist moiety incorporates the unnatural amino acid Aib and long-chain fatty acid modifications to enhance stability and elongate the half-life (Figure 5) ^[8].

Both oral and subcutaneous injection formulations has been developed for amycretin. Amycretin has successfully completed phase I/II trials and is advancing to phase III in 2026. Clinical data showed that oral Amycretin resulted in dose-dependent weight loss over a 12-week treatment period, with an average weight loss of 13.1% at a dose of 2 × 50 mg. In individuals receiving weekly subcutaneous injections of Amycretin (20 mg, 36 weeks), an estimated weight loss of up to 22.0% was observed^[8].

Besides clinical efficacy in weight-loss, amylin-based therapeutics offers milder gastrointestinal side effects and better preservation of lean body mass. Strong performance in clinical trials, combined with the growing demand in the weight management market, positions amylin-based pharmacotherapy at the forefront of metabolic drug development. Current research and development efforts in amylin programs are primarily concentrated in the following areas ^[9,10].

(1) Ultra-long-acting amylin therapeutics: longer half-time could be facilitated by modifications like lipidation, or drug-release technologies. E.g., MET-233i is a long acting amylin analog with 19-day half-life and enables monthly dosing.

(2) Oral and small-molecule approaches: oral administration of amylin drugs can be achieved through absorption enhancer (such as SNAC combined with amycretin), or by developing orally available small-molecule AMYR agonists, in order to improve patient adherence.

(3) Combination and multi-target strategies: combining amylin drugs with other weight-loss medications, or developing multi-target amylin therapies, can optimize efficacy and tolerability. For example, the phase III candidate CagriSema (a combination of cagrilintide and semaglutide) has demonstrated more pronounced effects compared to either cagrilintide or semaglutide alone ^[1].

(4) Indication expansion: beyond obesity to cardiometabolic disease, NAFLD, bone metabolism, and potentially CNS disorders.

Overall, amylin-based therapies have demonstrated robust weight-loss efficacy in clinical trials. However, their long-term safety, inter-individual variability, and comparative positioning against GLP-1 and multi-agonist therapies require validation in large-scale, long-term studies, leaving their potential as a next-generation obesity therapy following GLP-1 unconfirmed.