Aqueous remote loading of setmelanotide in poly(lactic-co-glycolic acid) microspheres for long-term obesity treatment
Setmelanotide already treats rare genetic obesity — at the cost of a daily injection, often from childhood. Loading it into porous PLGA microspheres from plain water gave roughly a month of release, and body weight control that outlasted the appetite suppression that started it.
A depot releasing its contents slowly: the study loaded setmelanotide into blank polymer microspheres from water, and let charge do the work.
Setmelanotide works. For patients with rare genetic forms of obesity — POMC deficiency, leptin receptor deficiency — the eight-amino-acid cyclic analogue of α-melanocyte-stimulating hormone reaches the melanocortin-4 receptor and does what the broken pathway upstream can no longer do. The FDA approved it in 2020 under the name Imcivree.
The difficulty is not whether it works but what it asks. Setmelanotide has an elimination half-life of roughly eleven hours in humans, so the approved product is a daily subcutaneous injection, for a chronic condition, often beginning in childhood. No alternative that reduces the injection frequency has reached the market; Rhythm Pharmaceuticals has been testing weekly 20–30 mg forms in the clinic, but the formulation behind them has not been described.
A group at the University of Michigan, working with Tomi K. Sawyer of Courage Therapeutics, asked whether the peptide could instead be put inside a polymer depot and allowed to leave slowly. Their answer, published in the Journal of Controlled Release, is the first reported long-acting formulation giving roughly a month of controlled setmelanotide release, with body weight control to match, in a diet-induced obese mouse.
Loading a peptide without dissolving it in solvent
Poly(lactic-co-glycolic acid) — PLGA — is the workhorse polymer of injectable depots, but getting a fragile peptide into it has traditionally meant encapsulating the drug during manufacture, exposing it to organic solvents and shear. The alternative this work builds on is remote loading: make the microspheres empty first, then simply incubate them in an aqueous solution of the peptide and let the drug walk in by itself.
That works because of charge. Setmelanotide carries roughly two positive charges at neutral pH, and PLGA presents carboxylic acid end groups that are correspondingly anionic. The peptide’s cationic arginine side chains and the polymer’s acid groups attract one another, and the drug concentrates inside the particle from plain water, under mild conditions.
The team made three batches of blank microspheres differing only in how porous they were, adjusting the amount of trehalose porosigen — 100, 50 or zero microlitres — added to the inner water phase. Then they incubated each in peptide solution for 24 hours at 37 °C and measured what went in.
Porosity mattered a great deal. Drug loading came out at 6.3 ± 0.3%, 4.6 ± 0.2% and 2.2 ± 0.2% w/w for the high-, medium- and low-porosity formulations respectively, with encapsulation efficiency reaching about 63% at the top end. Electron microscopy showed why: the non-porous spheres had no internal network of larger pores for the peptide to travel through.
This was not what the same laboratory had seen with leuprolide, where porosity made no significant difference over the same interval. The authors attribute the discrepancy to charge — setmelanotide’s roughly +2 against leuprolide’s +1 — noting a comparable pattern reported for octreotide, which also carries more charge and also takes longer to complete its sorption. A more strongly charged peptide binds harder, moves more slowly, and therefore depends more on having open channels to move through.
Six weeks in a tube, a month in an animal
In vitro, the loaded microspheres released setmelanotide slowly and continuously over about six weeks — and here porosity largely stopped mattering, with the three formulations behaving much alike despite having taken up very different amounts of drug.
The in vivo picture was assembled by deconvolution of the pharmacokinetics following a single subcutaneous injection in diet-induced obese mice. The resulting absorption pattern was consistent with the in vitro release profile, with two differences worth noting: a lower initial burst, and a slightly faster overall rate. The correlation between the two was linear, which the authors take as strong evidence that the same release mechanism operates in both settings.
What the mice did
After one injection, the animals were followed for 30 days against a control group given drug-free microspheres.
Food intake fell relative to control, and stayed down for about 17 days before the effect gradually tailed off. Body weight fell over roughly 21 days. And the improvement in body weight relative to the vehicle group persisted for the entire 30-day study — outlasting the appetite suppression that appeared to start it. The pharmacokinetic profile tracked this closely, with Tmax also falling at day 17.
Even though the suppression of food intake was temporary, body weight control was persistent over 3 weeks.
The authors are careful about what that gap means. Reduced food intake, they write, possibly accounted for the initial change in body weight but did not explain the persistent effect; it is possible that a change in metabolic activity also contributed. That is offered as a hypothesis consistent with what is known of melanocortin peptides, not as a demonstrated mechanism, and the study does not resolve it.
What it establishes, and what it does not
The claim the work supports is specific and worth stating precisely: a peptide already approved for daily injection can be loaded into a polymer depot from plain water, at useful loading, and released over roughly a month — with a single injection producing measurable body weight control across that period in an obese mouse. The authors describe this as the first such report for setmelanotide, and as support for developing long-acting options for the patients who take it.
It is a formulation study in a murine model. It does not address human pharmacokinetics, dose, tolerability, or the injection-site behaviour of a PLGA depot in people. The persistence of the weight effect beyond the period of reduced eating is an observation with a candidate explanation, not a finding about metabolism. And the comparison that would matter most clinically — against the weekly forms already in trials — is not one this study was designed to make.
What it does do is make the case for the approach. Remote loading avoids the solvents and processing that make peptide encapsulation difficult, and it works here precisely because of a property setmelanotide already has: the positive charge it carries into the polymer with it.
Source
Shuying Wang, Griffin Downing, Karl F. Olsen, Tomi K. Sawyer, Roger D. Cone and Steven P. Schwendeman. “Aqueous remote loading of setmelanotide in poly(lactic-co-glycolic acid) microspheres for long-term obesity treatment.” Journal of Controlled Release, 2023, volume 364, pages 589–600. Elsevier. Received 23 March 2023; accepted 4 September 2023; available online 15 November 2023. DOI: 10.1016/j.jconrel.2023.09.015.
Affiliations: Department of Pharmaceutical Sciences and the Biointerfaces Institute, University of Michigan; Life Sciences Institute, University of Michigan; Department of Molecular, Cellular and Developmental Biology, University of Michigan; Department of Molecular and Integrative Physiology, University of Michigan; Courage Therapeutics, Newton, Massachusetts. Shuying Wang and Griffin Downing contributed equally. Corresponding authors: Steven P. Schwendeman and Roger D. Cone.
The underlying research is the work of the cited authors and their institutions. Maestro Chronicle provides the editorial presentation.