(T0930-03-16) Remote Loading of Setmelanotide in Poly(lactic-co-glycolic acid) Microspheres for Long-Term Obesity Control

Purpose: Setmelanotide (Imcivree^TM) was developed as a daily injectable therapeutic peptide for the treatment of rare forms of syndromic obesity, such as POMC deficiency and leptin receptor deficiency. The important option of poly(lactide-co-glycolic acid) (PLGA) controlled release microspheres has become more attractive for this class of drugs upon the discovery that net positively charged peptides can be remote-loaded rapidly from aqueous peptide solution into blank microspheres at high loading and encapsulation efficiency. Here we sought to remote-load setmelanotide in PLGA microspheres and examine its potential for long-term controlled release and body weight control.

Methods: The impact of varying levels of porosigen added to the drug-free microspheres was investigated with respect to morphology, drug loading and in vitro release profiles. For in vivo evaluation, we developed a diet-induced obese murine model by placing 4-week-old C57 mice on 60% high-fat-diet for 9 weeks and pre-conditioning with saline injections for a week prior to microsphere injection. The diet-induced obese murine model was then used to determine the pharmacokinetic profile of an optimal formulation and to evaluate long-term efficacy by monitoring the food intake and body weight of diet-induced obese mice for 1 month. A deconvolution method was applied to examine similarities between the in vivo absorption with kinetics of weight control and in vitro release.

Results: We discovered that increased density of the microspheres inhibited the progress of encapsulation of the setmelanotide dication. Remote loaded PLGA formulation encapsulated setmelanotide at as high as ~63% (~6.3% w/w loading) and exhibited slow and continuous peptide release over ~6 weeks in vitro largely independent of microsphere porosity. The obtained in vivo release pattern from deconvolution of the pharmacokinetics after subcutaneous microsphere injection was consistent with the in vitro release profile but with a lower initial burst release and overall slightly faster release rate. After a single injection of remote-loaded setmelanotide, continuous long-term inhibition of food intake and body weight control was observed over 17 and 30 days, respectively. The improvement in body weight control over drug-free microsphere vehicle-treated control groups matched well with the pharmacokinetic profile.

Conclusion: This study provides the first report of long-acting release formulation for 1-month controlled release of setmelanotide and body weight control in a diet induced obese murine model and supports the further development of long-acting treatment options for obese patients.

References: 1. Sophocleous, A. M., et al., The nature of peptide interactions with acid end-group PLGAs and facile aqueous-based microencapsulation of therapeutic peptides, J. Controlled Release, 172, 662-670 (2013). 2. Giles, M. B., et al., Efficient aqueous remote loading of peptides in poly(lactic-co-glycolic acid), Nat. Commun., 13 (1), 1-9 (2022).

Acknowledgements: This work was supported in part by NIH Grant 2R42DK127817-02. Roger D. Cone, Tomi K. Sawyer, and the University of Michigan have equity in Courage Therapeutics, and Roger D. Cone serves on the board of the company.

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