MVT-602 / Sumitomo Pharma - LARVOL DELTA

Unravelling the Regulation of the Kisspeptin Receptor (kiss1r) Through Its Interaction With G Protein-Coupled Estrogen Receptor (gper) (ENDO 2025) - "We have previously shown that pretreatment with estrogen potentiates gonadotropin secretion after administration of the potent kisspeptin receptor agonist TAK-448...These findings demonstrate that KISS1R and GPER heteromerization may not only influence KISS1R surface expression and agonist-induced Gq signal activity but could differentially modulate the agonist-induced endocytic trafficking profiles of KISS1R. These data highlight the regulatory role of receptor heterodimerization and trafficking in modulating KISS1R activity, providing insights for its potential use to treat endocrine disorders."

Endocrine Disorders

Unravelling the Regulation of the Kisspeptin Receptor (kiss1r) Through Its Interaction With G Protein-Coupled Estrogen Receptor (gper) (ENDO 2025) - "We have previously shown that pretreatment with estrogen potentiates gonadotropin secretion after administration of the potent kisspeptin receptor agonist TAK-448...These findings demonstrate that KISS1R and GPER heteromerization may not only influence KISS1R surface expression and agonist-induced Gq signal activity but could differentially modulate the agonist-induced endocytic trafficking profiles of KISS1R. These data highlight the regulatory role of receptor heterodimerization and trafficking in modulating KISS1R activity, providing insights for its potential use to treat endocrine disorders."

Endocrine Disorders

Structural basis for the ligand recognition and G protein subtype selectivity of kisspeptin receptor. (PubMed, Sci Adv) - "We further resolved the cryo-electron microscopy (cryo-EM) structure of KISS1R-Gq and KISS1R-Gi complexes bound to the synthetic agonist TAK448 and structure of KISS1R-Gq complex bound to the endogenous agonist KP54. The high-resolution structures provided clear insights into mechanism of KISS1R recognition by its ligand and can facilitate the design of targeted drugs with high affinity to improve treatment effects. Moreover, the structural and functional analyses indicated that conformational differences in the extracellular loops (ECLs), intracellular loops (ICLs) of the receptor, and the "wavy hook" of the Gα subunit may account for the specificity of G protein coupling for KISS1R signaling."

Journal

Structural basis for hormone recognition and distinctive Gq protein coupling by the kisspeptin receptor. (PubMed, Cell Rep) - "Here, we present cryo-EM structures of KISS1R bound to the endogenous agonist kisspeptin-10 and a synthetic analog TAK-448...This study reveals the molecular intricacies governing ligand binding and activation of KISS1R, while highlighting its exceptional ability to couple with Gq. Our findings pave the way for structure-guided design of therapeutics targeting this physiologically indispensable receptor."

Journal • Cognitive Disorders • Infertility • Sexual Disorders

Endocrine profile of the kisspeptin receptor agonist MVT-602 in healthy premenopausal women with and without ovarian stimulation: Results from two randomized, placebo-controlled clinical trials. (PubMed, Fertil Steril) - P=N/A | "MVT-602 induces LH concentrations of similar amplitude and duration as the physiological mid-cycle LH surge with potential utility for induction of oocyte maturation and ovulation during MAR."

Clinical • Journal • Gynecology

Advances in clinical applications of kisspeptin-GnRH pathway in female reproduction. (PubMed, Reprod Biol Endocrinol) - "More clinical trials should focus on the therapeutic effect of kisspeptin, its receptor agonist and antagonist in women with reproductive disorders, such as hypothalamic amenorrhoea, polycystic ovary syndrome, and endometriosis."

Journal • Review • Endometriosis • Gynecology • Polycystic Ovary Syndrome

Kisspeptin receptor agonist has therapeutic potential for female reproductive disorders. (PubMed, J Clin Invest) - "LH increases following MVT-602 were similar in PCOS and healthy women, but advanced in HA (P = 0.004). In keeping with the clinical data, MVT-602 induced more potent signaling of KISS1R-mediated IP1 accumulation and a longer duration of GnRH neuron firing than KP54 (115 vs. 55 minutes; P = 0.0012).CONCLUSIONTaken together, these clinical and mechanistic data identify MVT-602 as having considerable therapeutic potential for the treatment of female reproductive disorders.TRIAL REGISTRATIONInternational Standard Randomised Controlled Trial Number (ISRCTN) Registry, ISRCTN21681316.FUNDINGNational Institute for Health Research and NIH."

Journal • Polycystic Ovary Syndrome • Women's Health

Pharmacokinetic and pharmacodynamic modeling of the metastin/kisspeptin analog, TAK-448, for its anti-tumor efficacy in a rat xenograft model. (PubMed, Biopharm Drug Dispos) - "Here, we developed pharmacokinetic-pharmacodynamic (PK/PD) models of TAK-448 and leuprorelin acetate (TAP-144) in a rat Vertebral-Cancer of the Prostate (VCaP) androgen-sensitive prostate cancer xenograft model to quantitatively assess and compare the anti-tumor effects of both drugs. In addition, model inference, by incorporating a hormone-independent inhibition pathway of TAK-448 into the PK-PD model, suggested that such a direct inhibition pathway for TAK-448 cannot be excluded, as also indicated by in vitro studies, but its EC would be approximately three orders of magnitude higher than that of the hormone-dependent pathway. This study helps to understand the potential and mechanism of TAK-448 as a prostate cancer treatment."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

The enhancement of subcutaneous first-pass metabolism causes non-linear pharmacokinetics of TAK-448 after a single subcutaneous administration to rats. (PubMed, Drug Metab Dispos) - "A dose-dependent enhancement of first-pass metabolism appears to contribute to the less than dose-proportional non-linear pharmacokinetics of TAK-448 after SC administrations to rats. SIGNIFICANCE STATEMENT: N/A."

Journal • PK/PD data • Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Investigation of disposition for TAK-448, a synthetic peptide of kisspeptin analog, in rats and dogs using the radiolabeled TAK-448 suitable for pharmacokinetic study. (PubMed, Xenobiotica) - "6. These results suggest that TAK-448 has an acceptable pharmacokinetic profile for clinical evaluation and development, and demonstrate that the synthesized [D-Tyr-C]TAK-448 used in this study represents a favorable labeling position to evaluate disposition properties of this compound."

Journal • PK/PD data • Preclinical