Clinical Trials: Uterine Fibroids

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1 Clinical Trials: Uterine Fibroids Phyllis C. Leppert, MD, PhD President, The Campion Fund Professor Emerita of Obstetrics and Gynecology Duke University School of Medicine

2 Uterine fibroids: a connective tissue disease Collagen deposition prominent in fibroids, important in their natural history. Flake, Moore, Sutton, Kissling,Horton, Walmer, Robboy, Dixon Obstet Gynecol Int Extracellular matrix especially altered type I, III and V collagen accumulates. Leppert, 2004 Type I/type III ratio is decreased and suggests alterations in collagen metabolism in fibroids. Jayes, Feng, Leikin, Leppert, in preparation, 2016 Med12 gene is involved in the pathogenesis Aaltonan, 2011

3 Courtesy of Stewart Cramer

4 Collagen Fibrils Myometrium Leiomyoma Treatments must target the accumulated collagen Leppert et al. Fertil Steril, 2004

5 An Open Letter to the Food and Drug Administration Regarding the Use of Morcellation Procedures in Women Having Surgery for Presumed Uterine Myomas Signed by 26 obstetrican/gynecologists with expertise on the topic and published in the Journal of Minimally Invasive Gynecology: Volume 23, Issue 3, March April 2016, Pages Six signees were invited to a meeting at the FDA (WH Parker UCLA, AM Kraunitz U of Florida, E. Chalas Winthrop U, D Clarke-Pearson UNC, P. Leppert Duke, Carla Dionne National Uterine Fibroid Foundation) Meeting concluded with the decision to update the Black Box warning- currently in progress

6 Clinical Trial Phases (Steps) Phase I Phase II Phase III Phase IV Test new drug on small group of people for safety, safe dose range, discover side effects Drug given to large group for effectiveness and safety Drug given to large group to confirm effectiveness, monitor side effects and compare to common treatments, collect information for safe treatment regimen Studies done after drug is on the market: gather long-term effects information

7 Presentation Overview Review 2 recently completed clinical trials Phillips (Sonalleve) Insightec (ExAblate) Present 5 ongoing clinical trials SONATA Study (completion October 2019) Elagolix clinical trials (completion May 2019) Proellex (Telapristone) study (completion 2017) Purified bacterial collagenase study (Xiaflex *) Esmya * (Ulipristal) study (completed early 2018)

8 High-intensity Focused Ultrasound

9 Clinical Trials of Efficacy of Newer Focused Ultrasound Equipment Phillips (Sonalleve) Insightec (ExAblate) Fibroids are treated by heat coagulation destroys cells and some extracellular matrix proteins and glycoproteins and contraction of collagen Focused US generated heat: US energy is absorbed into the tissue and increases the tissue temperature. Fibroids are treated by heat coagulation destroys cells and some extracellular matrix proteins and glycoproteins and contraction of collagen

10 Sonalleve Study Recruitment is complete: 224 subjects 12 month follow up in progress Estimated study completion: April 2019 Outcomes measured: Fibroid related symptoms and their severity Need for other treatment Menstrual blood loss Return to activity

11 ExAblate Study FDA approved Insightec s next generation Exablate fibroid treatment system on October 7, 2015 Allows treatment options for women who desire to maintain fertility. The approval is based on accumulated, documented clinical data on 118 patients pregnancies post Exablate MRgFUS treatments.

12 Radiofrequency ablation of fibroids Sonata System (previously VizAblate) made by Gynesonics, Inc. Sonography-guided transcervical ablation of uterine fibroids Fibroid tissue is ablated by heat generated by medium frequency alternating current Small ultrasound probe and the tip of a radiofrequency device No data on effects on collagen

13 SONATA Study Safety and Efficacy Study Outcomes: Reduced menstrual bleeding Need for subsequent treatment by other methods Change in fibroid size Change in symptoms Estimated study completion date: October, 2019

14 Elagolix * (a GnRH antagonist) for fibroid treatment * AbbVie, Inc.

15 Elagolix clinical trials conducted by AbbVie, Inc. Two Phase 3 parallel double blind, placebo controlled trials. One with Elagolix alone and one with Elagolix and hormone add-back treatment (estradiol/norethendione) given orally. Each trial will have 400 subjects and will last 6 months. Outcomes; heavy bleeding, change in fibroid size, symptoms. Estimated completion date: May, 2018

16 Selective Progesterone Receptor Agonists and Modulators SPRMs Progesterone and Progesterone receptor complexes reduce apoptosis and promote fibroid cell proliferation and there is evidence in cell culture that they decrease collagen production. Telapristone Ulipristal acetate

17 Telapristone

18 Proellex (Telapristone) for fibroid treatment Selectively blocks the progesterone receptor Phase 2 extension clinical trial in progress Outcomes: Heavy bleeding, fibroid size Study both oral and vaginal administration Vaginal delivery study to be completed 2017 Oral delivery study to be completed later in 2017 Repros Therapeutics Inc. is developing the drug

19 Urlipristal acetate

20 New phase 3 clinical trials are ongoing Current outcomes show: Reduced fibroid size Control of symptoms of heaving bleeding and pain Allergan will market the drug

21 Esmya : Fibristal TM (Ulipristal) 5mg dosage for the treatment of uterine fibriods. FDA approval anticipated in early 2018 Allergan will market the drug

22 Purified bacterial collagenase (Xiaflex *) Phase 1 study being conducted at Johns Hopkins to test this injected drug to treat fibroids FDA IND number Directly targets the collagen of fibroids The study is sponsored by Advanced Biofactures Corporation and will be presented in more detail at this meeting. * Endo Pharmaceuticals

23 Upshot, Recap and a Parting Thought Progress has been made in treatment options for fibroids. Clinical trials are in progress and will be finished soon. Further study is indicated to determine optimal treatment for individuals Physicians and scientists should seriously think about combining various therapies to maximize treatment. Multiple drugs and procedures will be needed. Dr. Darlene Taylor is developing a way that multiple drugs can be injected into fibroids. This type of approach holds promise.