Areas of Future Research in Fibroid Therapy

Home , Mifepristone, Telapristone, Vilaprisan

9/18/18

Cumulative Incidence of Fibroids over Reproductive Lifespan

RFTS Areas of Future Research Blacks Blacks UFS

Whites in Fibroid Therapy CARDIA Age 33-46

William H. Catherino, MD, PhD

Whites Professor and Chair, Research Division Seveso Italy Uniformed Services University Blacks Whites Associate Program Director Sweden/Whites (Age 33-40) Division of REI, PRAE, NICHD, NIH

The views expressed in this article are those of the author(s) and do not reﬂect the ofﬁcial policy or position of the Department of the Army, Department of Defense, or the US Government. Laughlin Seminars Reprod Med 2010;28: 214

Fibroids Increase Miscarriage Rate Obstetric Complications of Fibroids

Complication Fibroid No Fibroid OR Abnormal labor 49.6% 22.6% 2.2 Cesarean Section 46.2% 23.5% 2.0 Preterm delivery 13.8% 10.7% 1.5 Breech position 9.3% 4.0% 1.6 pp Hemorrhage 8.3% 2.9% 2.2 PROM 4.2% 2.5% 1.5 Placenta previa 1.7% 0.7% 2.0 Abruption 1.4% 0.7% 2.3

Guben Reprod Biol Odds of miscarriage decreased with no myoma comparedEndocrinol to myoma 2013;11:102 Biderman-Madar Arch Gynecol Obstet 2005;272:218 Ciavattini J Matern Fetal Neonatal Med 2015;28:484-8 Not Impacting the Cavity Coronado Obstet Gynecol 2000;95:764 Kramer Am J Obstet Gynecol 2013;209:449.e1-7 Navid Ayub Med Coll Abbottabad 2012;24:90 Sheiner J Reprod Med 2004;49:182 OR = 0.737 [0.647, 0.840] Stout Obstet Gynecol 2010;116:1056 Qidwai Obstet Gynecol 2006;107:376

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Best Studied Therapies Hysterectomy Option over Time Surgical Radiologic Medical >100 years of study Hysterectomy Open myomectomy

GnRH agonists 25-34 years of study

Endometrial Ablation GnRH agonists 20-24 years of study Laparoscopic myomectomy Uterine artery embolization Retinoic acid 10-19 years of study Uterine artery obstruction SPRMs: Mifepristone, ulipristal Robotic myomectomy GnRH antagonists

5-9 years of study Cryomyolysis MRI-guided high frequency ultrasound SPRMs: Asoprisnil, Telapristone, Laparoscopic ablation Vilaprisan SERMs: Tamoxifen, Raloxifene, Letrozole, Genistein Pitter MC, Simmonds C, Seshadri-Kreaden U, Hubert HB. JMIR 2014;3: Jacoby VLObstet Gynecol 2009;114:1041-8

2011 2012 2013 2014 2015 2016 2017 2018 Elagolix Vilaprisan Vilaprisan Vilaprisan Ulipristal Ulipristal Ulipristal Ulipristal Ulipristal Ulipristal Ulipristal Ulipristal Leuprolide Leuprolide Leuprolide Leuprolide Leuprolide Leuprolide Leuprolide Leuprolide

Mifepristone Mifepristone Mifepristone Mifepristone Mifepristone Mifepristone Mifepristone Mifepristone Cetrorelix Cetrorelix Cetrorelix Cetrorelix Cetrorelix Retinoic Acid Retinoic Acid Retinoic Acid Retinoic Acid Retinoic Acid Retinoic Acid ECGC ECGC ECGC Berberine Berberine Tranilast Halofuginone Halofuginone Halofuginone >100 pubs

Levonorgestrel Levonorgestrel Levonorgestrel Levonorgestrel Levonorgestrel 70-99 pubs

Medical Therapy Triptorelin Triptorelin Triptorelin Triptorelin Triptorelin 10-69 pubs Letrozole Letrozole Letrozole Letrozole 1-9 pubs AG1478 AG1478 Last Pub Simvastatin Tamoxifen 2001 Goserelin Goserelin Goserelin Goserelin Targretin 2004 Raloxifene Raloxifene Raloxifene Raloxifene Pioglitazone 2005 Tibolone Tibolone Tibolone Tibolone Resveratrol 2005 Asoprisnil Asoprisnil Asoprisnil Asoprisnil E. alatus 2006 Liarozole Liarozole TKS050 2007 Celecoxib Celecoxib Ciglitazone 2007

Telapristone Telapristone Telepristone Isoliquiritigenin 2008 Lynesterol Lynesterol Curcumin 2011 Methoxyestradiol Methoxyestradiol Fulvestrant 2011 Buserelin Buserelin Perfenidone 2011 CDB-4124 2011

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Leuprolide Acetate

GnRH Analogues 10, patient reported - VisualAnalog Scale: 1

Palomba Fertil Steril 1998;70:111

Elagolix

Selective Progesterone Receptor Modulators

Archer Fertil Steril 2017;108:152

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Chemical Structures: Selective Progesterone Receptor How do sPRMs work? Modulators (SPRMs)

CH3 O OO N SS F FF F H3 C OCH3 F H OH F OCCH3 FF O CH3

N H3 C OH O OO C C CH3 Ulipristal Vilaprisan

CH3 OCH3 HO N

N O O H3 C

OCH2 CH3 Mifepristone OCH3 CH2 OCH3

O Progesterone O Telapristone Asoprisnil

Bouchard Fertil Steril 2011;96:1175

Mifepristone Clinical efficacy of each SPRM for fibroid N = 14 treatment Age: 40.8 BMI: 25.9 Decrease in fibroid size: 28% Engman Hum Reprod 2009;24:1870

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PEARL I: Asoprisnil Ulipristal Controls bleeding faster than Placebo Bleeding Suppression Uterine Volume

Donnez NEJM 2012;366:409

Chwalisz Fertil Steril 2007;87:1399 Donnez N Engl J Med 2012;366:409

PEARL II: Ulipristal Controls Bleeding Faster Vilaprisan: Optimal Dose than Leuprolide Acetate approximately 1-2 mg to induce Non-Bleeding Event

Donnez NEJM 2012;366:421-32

Donnez N Engl J Med 2012;366:421 Schütt Hum Reprod 2016;31:1703

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Vilaprisan: 1-2 mg decreases mean number of Bleeding Days Potential Future Therapies

Schütt Hum Reprod 2016;31:1703

Simvastatin Retinoic Acid

• hmg-CoA • Differentiating inhibitor agent • Hyperlipidemia • Relatively toxic therapy • Compounds that • Antitumor increase properties intracellular retinoic acid available for study

Catherino WH, Malik M. Fertil Steril 2007;87:1388 Borahay J Biol Chem 2014;289:35075 Ben-Sasson Fertil Steril 2011;95:2080 Borahay Am J Obstet Gynecol 2015;213:196.e1-8 Gilden Fertil Steril 2012;98:1557

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Vitamin D Green Tea Extract

• Has • High therapeutic antiproliferative index and apoptotic • Consumption function associated with • Vit D depletion lower cancer associated with incidence high risk of fibroids

Halder Biol Reprod 2012;86:116 Zhang Am J Obstet Gynecol 2010;202:289 Halder Biol Reprod 2013;89:150 Roshdy Int J Womens Health 2013;5:477

Berberine Tranilast

• Chinese herb • Anti-allergic • Anti-inflammatory • Inhibits mast cell • Used to treat degranulation chronic • Inhibits release of inflammatory inflammatory conditions mediators • Prevents keloid tumor formation

Chuang Reprod Sci 2017;24:1005 Wu Fertil Steril 2015;103:1098 Islam Fertil Steril 2014;102:597

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Cabergoline / Aromatase Inhibitor Summary

500 Before • Dopamine After receptor agonist • There is an increasing interest in moving from surgical • Combined with to medical management. 0 aromatase Co ntro l Ca berg oli ne • GnRH analogues and SPRMs effectively decrease inhibitor menorrhagia and leiomyoma size • No value in • Novel therapies that function without regulating addition of gonadal hormones are currently under investigation cabergoline

Vahdat Eur J Obstet Gynecol Reprod Biol 2016;206:74 Sayyah-Melli Eur J Obstet Gynecol Reprod Biol 2017;210:257

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