Long-acting leptin agonists are currently preclinical. So, same as long-acting GH or long-acting insulin or long-acting GLP-1, there may soon be a long-acting leptin. Much better than the currently available metreleptin. Furthermore, mibavademab (an allosteric agonist antibody) developed by Regeneron will also be available hopefully soon (couple of years?). These drugs will hopefully be much cheaper than metreleptin, which runs over 1000$ a day for a therapeutic dose which is just insane.
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I have been researching for so long I totally forgot… yes I found this study a while back. I wish I could find another trial to be part or or find a dr willing to prescribe it off label. I actually just found a study that might still be recruiting… would just suck to get the placebo lol
Just saw this thread and what a fascinating read/stuff. Thanks for posting it here and thanks for all the work you put into it. I’m sure my limited English vocabulary does it no favors but by far the most intriguing, useful and helpful information I have ever read or ran into with regards to health and longevity.
Thank you, again!
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I found these. Have you seen anything other than these?
Despite the multifaceted role of leptin for energy homeostasis and its broad therapeutic potential, the FDA/EMA-approved metreleptin constitutes the only leptin drug to date. To translate the promising results from previous studies on murine PASylated leptin with improved solubility and extended plasma half-life using PASylation technologya biological alternative to PEGylationwe have developed a second-generation human leptin drug candidate and tested it rigorously in vitro and in vivo . To this end, the exposed hydrophobic Trp residue at position 100 in human leptin was replaced by Gln, which, together with the genetic fusion with a 600-residue PAS polypeptide, yielded a protein with high solubility, folding stability and receptor-stimulatory activity. In a pharmacokinetic (PK) study with wild-type mice, this modified human leptin showed an extended plasma half-life of 18.8 ± 3.6 h after subcutaneous (s.c.) injection. Furthermore, leptin-deficient mice were dosed s.c. with the modified human leptin carrying two different PAS fusion tags, PAS#1 or P/A#1, each comprising 600 residues. After only four doses, the disease phenotype, including morbid adiposity, hyperphagia, and hepatic steatosis, was completely reversed by both PASylated leptin versions, but not by the non-PASylated leptin if administered at the same dose. To assess its tissue distribution, P/A(200)-huLeptinW100Q was doubly labeled with two fluorescent dyes, which were specifically attached to the leptin and the PAS moiety, respectively. Analysis of relevant mouse organs by light sheet fluorescence microscopy after clearance revealed colocalized signals in the kidney and liver, thus indicating general stability of the PAS-leptin fusion protein in vivo . However, discrete signals were observed in the hypothalamic region, only with leptin detectable in the choroid plexus, which implies cleavage of the PAS tag during transcytosis across the physiological barriers. This study should pave the way toward a second-generation leptin drug enabling prolonged dosing intervals.
"Leptin and leptin receptor play an important role in body weight maintenance and energy homeostasis. Leptin’s involvement in many peripheral biological functions, as well as in autoimmune diseases and cancer increased the interest for the design and development of leptin-based drugs acting as leptin-activity modulators.
The studies reported in this review cover the main developed strategies to date to modulate leptin signaling including leptin muteins, peptide-based leptin receptor antagonists, neutralizing antibodies and nanobodies.
The majority of the reported molecules act as ObR antagonists and are mutants of the full native protein (SHLA, Lan-2, and Lan-1) and peptide fragments (LPrA2, Allo-aca, and D-ser, LDFI) relating to single receptor-binding site. Although these strategies were demonstrated as quite efficient in various cancer models, in some cases they resulted in a significant unwanted weight gain in mice upon treatment.
The ability of the leptin receptor to interact with other receptor systems (epidermal growth factor receptor (EGFR), estrogen receptor alpha (ERα), insulin-like growth factor I receptor (IGF-IR)) may offer the opportunity to overcome this limit by uncoupling leptin’s central and peripheral functions and to design more selective leptin receptor antagonists, with an improved therapeutic action.
All these findings might contribute to a better knowledge of the complex biological mechanisms responsible for leptin activities and pave the way for the future development and clinical application of novel and more effective leptin receptor modulators able to prevent the undesired metabolic side effects."
Source: Leptin-Activity Modulators and Their Potential Pharmaceutical Applications - PMC
Also:
“Recent studies indicate that glucagon-like peptide (GLP)-1 inhibits appetite in part through regulation of soluble leptin receptors. Thus, during weight loss maintenance, GLP-1 receptor agonist (GLP-1RA) administration may inhibit weight loss-induced increases in soluble leptin receptors thereby preserving free leptin levels and preventing weight regain.”
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I experimented with high dose melatonin (40mg) and it significantly raised my T, E and prolactin. No impact on SHBG.
I take about 1.6g per night.