DEVELOPMENT OF HYDROXYSTEROID (17-BETA) DEHYDROGENASE TYPE 1 (HSD17B1) INHIBITOR FOR ENDOMETRIOSIS

Niina Saarinen1,2, Tero Linnanen1, Jasmin Tiala1, Camilla Stjernschantz1, Leena Hirvelä1, Taija Heinosalo2, Bert Delvoux3, Andrea Romano3, Gabriele Möller4, Jerzy Adamski4, Matti Poutanen2, Pasi Koskimies1 1Forendo Pharma Ltd, Finland; 2Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Finland; 3Department of Obstetrics and Gynaecology; GROW, School for Oncology and Developmental Biology; Maastricht University Medical Centre, The Netherlands; 4Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, Germany

BACKGROUND OBJECTIVE Local activation of estrogens in endometriosis tissue The main objective of the present work was to assess is considered important for growth of the lesions. the preclinical efficacy of the novel HSD17B1 inhibitor, Hydroxysteroid (17-beta) dehydrogenase type 1 FOR-6219 (HSD17B1) is expressed in endometriosis tissue and converts the biologically low-active estrogen, estrone (E1), to the highly active estradiol (E2), while hydroxysteroid (17-beta) dehydrogenase type 2 (HSD17B2), catalyzes the opposite reaction. In contrast to eutopic endometrium, in endometriotic lesions the HSD17B1/HSD17B2 expression ratio is increased and E2 levels are higher than those of E1 throughout the menstrual cycle. Thus, inhibition of HSD17B1 is considered as a feasible strategy for lowering local E2 production in endometriosis. MAIN RESULTS FOR-6219 inhibits human HSD17B1 Ø FOR-6219 is a potent and FOR-6219 does not trigger estrogenic fully selective inhibitor of response in immature rat uterine human HSD17B1 over growth assay HSD17B2 Ø FOR-6219 does not bind to estrogen receptor α or β, and exhibits no estrogen-like response in immature rat uterotrophic assay Ø FOR-6219 inhibits HSD17B1 in cynomolgus monkey, dog and rabbit i.e. in species FOR-6219 does not inhibit other HSD17Bs allowing toxicological and FOR-6219 inhibits selectively HSD17B1 HSD17B2 HSD17B3 HSD17B4 HSD17B7 HSD17B14 HSD17B5 pharmacodynamic studies orthologs present in other species AKR1C3 Cynomolgus Dog Rabbit Rat/ IC50 (nM) >10000 >5000 >5000 >5000 >5000 920 monkey Mouse Inhibition % Ø FOR-6219 inhibits E2 at 1µM 0 0 0 0 14 61 formation from E1 in IC50 (nM) 290 48 148 >10000 endometriosis tissue ex vivo CONCLUSIONS FOR-6219 inhibits E2 formation in ü FOR-6219 is a novel and potent HSD17B1 endometriosis inhibitor and a suitable candidate for drug development for endometriosis ü FOR-6219 is highly specific for human HSD17B1 and selectively inhibits the orthologs present in other species ü Non-clinical regulatory studies needed for the first in-human trials have been completed