Disclosure Principal Investigator, The ULTRA Study Nationwide - PowerPoint PPT Presentation

Disclosure Principal Investigator, The ULTRA Study Nationwide registry of laparoscopic radiofrequency ablation New Treatments For Funded by Acessa Health under contract with UCSF *Investigator Initiated Research (IIR) Uterine Fibroids *Study design, implementation, analysis, and publication are independent of Acessa Health Vanessa Jacoby, MD, MAS Associate Professor Obstetrics, Gynecology, & Reproductive Sciences University of California, San Francisco Outline Impact of Fibroids • 30% of premenopausal women • Medical Management • Antifibrinolytics • Up to 80% of African-American women • Hormonal modulation • Complementary treatments • #1 reason for hysterectomy (250,000/year) • Devices • $34 billion/year to care for women with fibroids. • Focused Ultrasound • Radiofrequency ablation • $17 billion for lost work and disability after surgery Cardozo et al, AJOG, 2012 March

Antifibrinolytic: Tranexamic Acid Tranexamic Acid: Pivotal RCT • Nonhormonal medication for heavy menses • Binds to plasmin to inhibit fibrinolysis N=297 2% decrease 26% decrease 39% decrease Freeman et al, AJOG, 2011, pg 319. e1-7 Tranexamic Acid RCTs: Tranexamic Acid: Limitations Subgroup with Fibroids in Two Pivotal Trials With fibroids, N=147 • Unknown fibroid size, number, location in subgroup • Excluded if MD thought fibroids better for surgery 44% decrease • Side effects: headache, GI • Potential thrombotic risk (VTE) • Not observed in trials Without fibroids, N=224 • Women on OCP and others with VTE risk 36% decrease have been excluded Freeman et al, AJOG, 2011, pg 319. e1-7 Eder et al, Women’s Health, 2013

Medical Management: Hormonal Manipulation Progesterone Receptor Modulators (PRM) • Decrease fibroid volume • Induce apoptosis, suppress vascularization, reduce collagen deposition • Suppress ovulation, but not estrogen levels Progesterone Estrogen • Ulipristal Acetate • Not available currently in U.S. for fibroids • Pivotal trials recently completed for FDA approval (Watson Pharmaceuticals, NCT02147197) New Drug Targets: Selective hormone modulation Progesterone Receptor Modulators: Ulipristal Trials: PEARL I and II Ulipristal (PEARL I and II) Ulipristal vs. Placebo Ulipristal vs. Lupron • Two European trials (85-90% white participants) U 5mg Placebo U 5mg Lupron • Placebo vs. Ulipristal (n=242) N=95 N=48 N=93 N=93 PBAC<75 • Lupron vs. Ulipristal (n=307) (normal) 91% 19%* 75% 80% • Participants with heavy bleeding, anemia, uterus Amenorrhea 73% 6%* 90% 89% <16 weeks (largest fibroid <10cm) Change in -21% +3%* -36% -53% fibroid • Received13 weeks of medication prior to surgery volume Moderate to 11% 40%* severe hot flashes * p<.05 compared with 5mg Donnez et al, NEJM, 2012: 366:421-32. Donnez et al, NEJM, 2012

Long-Term Ulipristal PRM Endometrial Changes Endometrial Changes: PEARL IV • Trial of 4 treatment periods, 12 weeks each with • PRM-associated endometrial changes (PAEC) menses in between (spontaneous or northindrone) • N=230 on 5mg daily, N=221 on 10mg • PAEC occurs in 8-20% of women • EMB prior to treatment, all normal • During study, EMB after each 12 week cycle • Concern for possible long-term • Simple hyperplasia, n=3 safety and transformation to endometrial hyperplasia • Complex atypical hyperplasia, n=1 during study, N=1 at 3 month f/u • PAEC seems to regress • Endometrial adenocarcinoma, n=1 spontaneously after stopping drug Donnez et al, Fert Ster, Jan 2016 GnRH Antagonist: Elagolix GnRH Antagonist: Elagolix • Suppresses pituitary-ovarian axis Reduction in blood • NOT Lupron: oral dosing, no hormone “flare” loss from baseline to last month of • Phase 2 randomized trial (N=271, 74% African- treatment American/black): Improvement in fibroid • Premenopausal women, bleeding >80cc/cycle, symptoms and QOL in uterine volume <2,500cc some, not all groups • 3 month treatment, 200-600mg, QD or BID Hot flashes: Elagolix alone 46-63% • 2 groups with add back (daily vs. cyclic Elagolix/add back 19-27% Placebo12% progestin) Archer et al, Fert Steril, July 2017

Aromatase Inhibitors: Letrozole: Decreases Fibroid Volume letrozole and anastrozole • Blocks action of aromatase enzyme in ovaries and peripheral tissue, including fibroids Fibroid volume in cc Fibroid Aromatase 46% Androgens Estrogen decrease Enzyme Parsanezhad et al, Fert Ster: Jan 2010: 93:1 Aromatase Inhibitors Complementary Treatments • Side Effects • Estrogen levels in serum remain normal • No hot flashes • Limitations • Small, uncontrolled trials, none in U.S. • No assessment of fibroid symptoms • Long Term Risks • Anti-inflammatory • Anti-proliferative • Unknown for premenopausal women • Antioxidant • Concern for osteoporosis because postmenopasual women • Animal and in vitro with breast cancer on AIs have increased risk of fracture – Inhibit proliferation and compared tamoxifen. induce apoptosis in fibroid cells Epigallocatechin (EGCG) Zhang et al, Fertil Steril 2010 and AJOG 2010

Complementary Treatments Green Tea Randomized Trial • Placebo-controlled trial N=39 • EGCG 800mg vs. Placebo • Fibroid symptoms • Hb (11.7 to 12.4 (g/dL) • Fibroid volume 33% -No information on baseline fibroid volume -No U.S. data Roshdy et al, Jo Women’s Health, 2013 Vitamin D Vitamin D: Epidemiologic Evidence • Women with sufficient levels of vitamin D (>20ng/mL) • Bone health AND…. less likely to have uterine fibroids • Calcium hemostasis • Reduces cell proliferation (OR 0.68, CI 0.48-0.96), N=1,036 • Increases apoptosis Baird et al. Epidemiology 2013;24:447-53 • Regulates extracellular matrix (ECM) • Regulates gene • Women with vitamin D deficiency more likely to have transcription of ER/PR fibroids ( OR 2.5, CI 1.2-4.9), N=384 Paffoni et al. J Clin Endocrinol Metab 2013;98:E1374-8 May protect against: • Cardiovascular disease • Inverse relationship between vitamin D and fibroid size • Cancer (breast, colorectal) Sabry et al. Int J Womens Health 2013;5:93-100 • Autoimmune disease • Uterine fibroids

MR Guided Focused Ultrasound Fibroid Devices (MRgFUS) FDA approved 2003, very limited availability across U.S. • Unlike new drugs, FDA does not require comparative trials for new devices • Lower quality evidence for devices vs. drugs when enter market •Focused ultrasound beam heats tissue to 150-185 0 F •Coagulative necrosis occurs What is MRgFUS? MRgFUS vs. UAE UAE MRgFUS Ionizing radiation X Hospital admission X (75%) A. B. Return to normal 7-10 days 1-3 days activities nonperfused volume (NPV) Potential for ovarian X failure Post-procedure X fever/infection C. D.

MRgFUS Symptom Improvement MRgFUS Outcomes Study N NPV Shrinkage Reoperation Largest trial to date (n=359) No comparison group Stewart et al 359 Variable 20% average Depends on NPV Low treatment volumes 2007 ( 24% at 2 years for AE: abdominal pain (33%) 45% NPV) skin burns (5%) Gorny 45% 2011 130 N/A 7.4% at 12 mo LeBlang 80 55% 31% at 6 mo N/A 2010 Funaki 2009 91 40% at 24 mo 15% at 34 mo Stewart EA, Gostout B, et al, Obstet Gynecol, Aug 2007 Placebo-controlled Trial of MRgFUS Pregnancy after MRgFUS 54 pregnancies (51 women) Pilot, N=20 Symptom severity score Ongoing 20% (11/54) Delivered 41% (22/54) TAB 13% (7/54) Antepartum SAB 26% (14/54) hospitalization -13 18% (4/22) -31 Placenta previa 9% (2/22) Term (14/15) p=.90 p=.20 Rabinovici, et al, Fertility and Sterility, January 2010 Jacoby V, et al, Fertil Steril, March 2016

FIRSTT Study: UAE vs. MRgFUS Radiofrequency Ablation • RCT (n=57) and parallel cohort (n=34) • Compared outcomes within 6 weeks of procedure • No difference in quantity or quality of Aes MRgFUS: less pain, lower use of opioids/NSAIDS, faster recovery (4 vs. 8 days, p<.001) UAE: Faster procedure (139 vs. 405 minutes, p<.001) Barnard et al, AJOG, May 2017 Radiofrequency Ablation The Radiofrequency Ablation Device • Fibroids identified with • FDA approved for fibroids November 2012 ultrasound (1cm incision) (Acessa) • Radiofrequency (RF) probe placed under ultrasound guidance (3mm incision) Generator with Foot Pedal • Monopolar RF energy delivered to fibroids • Tissue heats to 100 0 C to cause coagulative necrosis 3mm RF Handpiece • Fibroid cells reabsorbed Laparoscopic Ultrasound

RF Ablation: Current Evidence RF Ablation: Current Evidence • Largest study, n=135 • Industry funded, FDA pivotal trial • Uncontrolled, all women treated with RF ablation Fibroid criteria •<14 week uterus •<6 fibroids •<7cm fibroid •<300cm3 volume 52% decrease in symptom Chudnoff et al, Green Jo, May 2013 score Chudnoff et al, Green Jo, May 2013 RF Ablation: Current Evidence RF Ablation: Current Evidence • Adverse events: 4% Change in Fibroid and Uterine Volume • Pregnancy (“not recommended” per FDA) from Baseline • Not studied in women who desire future fertility • Insufficient data on pregnancy outcomes Uterine Volume Fibroid Volume Treatment Failure 3 months -15% (CI 11-20)* -40% (CI 36-44)* • <1% at 1 year (1/135) 12 months -24% (CI 19-30)* -45% (CI 39-52)* • 4.4% at 2 years (6/129) • 4.5% at 3 years (4/88) • TOTAL 11/135=8% *P<.001 Chudnoff et al, Green Jo, May 2013 Guido et all, Health and Quality of Life Outcomes 2013, 11;139 Chudnoff et al, Green Jo, May 2013