1. Meeting of the Advisory Committee for Reproductive Health Drugs August 29, 2006 Barbara Wesley, M.D., M.P.H. Division of Reproductive and Urologic Products

2. 2 NDA 21-945 17α Hydroxyprogesterone Caproate (Gestiva) Proposed Indication u Gestiva is indicated for the prevention of preterm birth in pregnant women with a history of at least one spontaneous preterm birth Dosage & Administration u Gestiva is to be administered IM at a dose of 250 mg once a week beginning between 16-weeks 0-days (16 0 weeks) and 20-weeks 6-days (20 6 weeks) gestation to week 37 of gestation or birth

3. 3 Overview of Clinical Studies Study 17P-IF-001 u Randomized, vehicle-controlled study with target enrollment of 500 subjects  150 subjects enrolled and treated  Study terminated prematurely: recall of study drug Study 17P-CT-002  Principal efficacy and safety study  Terminated prematurely: crossed efficacy threshold  463 of 500 planned subjects enrolled and treated  17OHP = 310; vehicle = 153 Study 17P-FU  Follow-up for long-term health and development  278 subjects enrolled: 17OHP = 194; vehicle = 84

4. 4 Study 17P-CT-002 Design  Double blind, vehicle-controlled with subjects randomized 2:1 to 17OHP or vehicle Inclusion Criteria  History of spontaneous singleton preterm birth  Gestational age of 16 0 to 20 6 at randomization Main Exclusion Criteria included  Known major anomaly  Prior progesterone or heparin Rx in current pregnancy  Hx of thromboembolic disease  Maternal medical/obstetrical complications including  Current or planned cerclage  Hypertension requiring medication  Seizure disorder

5. 5 Study 17P-CT-002 Study Medications  17α-hydroxyprogesterone caproate (250 mg/mL) in castor oil, benzyl benzoate, and benzyl alcohol u Vehicle Dosing Regimen u Weekly IM injection through Week 36 6 or delivery Primary Efficacy Endpoint u Birth < 37 0 weeks Additional Efficacy Endpoints (post hoc) u Birth < 35 0 weeks and < 32 0 weeks u Composite index of neonatal morbidity  Death, RDS, bronchopulmonary dysplasia, Gr. 3 or 4 IVH, proven sepsis, necrotizing enterocolitis

6. 6 Overview of Subject Disposition Study 17P-CT-002 17OHP N=310 n (%) Vehicle N=153 n (%) Completed Treatment Withdrawn from Treatment Due to Adverse Event Lost to Follow-up 279(90.0) 27 (8.7) 6 (1.9) 4 (1.3) 139(91.0) 14(9.2) 3(2.0) 0

7. 7 Preterm Births <37 0 Weeks Gestation in ITT Population (Study 17-P-CT-002) u PTB rate of 54.9% in vehicle arm considerably greater than rate in other MFMU Network studies u PTB rate of 37.1% in 17OHP arm similar to PTB rate in control arms in another MFMU Network studies 17OHP N = 310 Vehicle N = 153 % Difference [Adjusted 95% Confidence Interval] Number (%) Preterm Births 115 (37.1%)84 (54.9%)-17.8% [-28%, -7%] Primary Efficacy Endpoint

8. 8 Percent of Preterm Births in Revised ITT Population (Study 17-P-CT-002) Confidence intervals adjusted for the interim analyses and the final analysis. To preserve overall Type I error rate of.05, p-value boundary of.035 used for the adjustment (equivalent to a 96.5% confidence interval). Age at Delivery (Weeks) 17OHP N=310 Vehicle N=153 % Difference [Adjusted 95% Confidence Interval] Percent Delivered < 37 0 37.154.9 -17.8%[-28%, -7.0%] < 35 0 21.330.7 -9.4% [-18.7%, -0.2%] < 32 0 11.919.6 -7.7% [-15.5%, 0.1%] < 28 0 9.410.5 -1.1%[-7.4%, 5.2%]

9. 9 Proportion of Enrolled Subjects Continuing to be Pregnant by Gestational Age

10. 10 Gestational Age (Weeks) at Delivery (Study 17P-CT-002) 17OHP N=306 Vehicle N=153 Median37.536.5 Mean36.235.2 Min, Max18.1, 41.520.3, 41.6 Difference between groups (mean) 1.0 week [95%CI: 0.3,1.5]

11. 11 Birthweight (Study 17P-CT-002) 17OHP N=301 Vehicle N=151 Mean Weight (gm)27602582 Gm Difference [95%CI] 178.2 [-13, 290] Birthweight n (%) <2500 gm 82 (27.2%)62 (41.1%) % Difference [95%CI] -13.8% [-23, -4.5] <1500 gm 26 (8.6%)21 (13.9%) % Difference [95%CI] -5.3% [-11.6, 1.1]

12. 12 Miscarriages, Stillbirths, and Neonatal Deaths (Study 17P-CT-002) u No net survival benefit Pregnancy Outcome 17OHP N=306 n (%) Vehicle N=153 n (%) Miscarriages (16 to <20 weeks) Stillbirths Neonatal Deaths Total Deaths 5(1.6) 6(2.0) 8(2.6) 19(6.2) 0 2(1.3) 9(5.9) 11(7.2)

13. Days from Onset of Treatment to Fetal or Neonatal Death Days to Fetal or Neonatal Death 50 100 150 1.0 Proportion Surviving 0.8 17OHP Vehicle

14. 14 of Literature Reports of Fetal Loss in Women Treated with 17-hydroxyprogesterone Caproate Study17OHP n N Vehicle n N LeVine (1964)3/157/15 Shearman (1968)5/275/23 Johnson (1975)3/230/27 Yemini et al. (1985)8/393/40 n = Number of fetal losses N = Number of subjects in treatment group From: Keirse MJ, Brit J Obstet Gynecol 1990; 97(2):149-54

15. 15 Composite Neonatal Morbidity (Study 17P-CT-002) Morbidity 17OHP N=295 n (%) Vehicle N=151 n (%) Death (live births only)8(2.6)9(5.9) Respiratory Distress Syndrome 29(9.9)23(15.3) Bronchopulmonary Dysplasia 4(1.4)5(3.3) Gr. 3/4 Intraventricular Hemorr. 2(0.7)0(0.0) Proven Sepsis 9(3.1)4(2.6) Necrotizing Enterocolitis 0(0.0)4(2.7) Composite Index of Morbidity*35 (11.9%)26 (17.2%) * No. subjects with one or more of the listed morbidities.

16. 16 Maternal Safety Findings (Study 17P-CT-002) u Adverse event (AE) data not collected in usual manner  Subjects asked if had any symptoms related to study medication u No maternal deaths u 3 reports of serious AEs ─ all in 17OHP group  Pulmonary embolus 8 days post delivery  Cellulitis at study medication injection site  Postpartum hemorrhage, respiratory distress, endometritis u 11 subjects discontinued because of an AE  7 (2.2%) in 17OHP group  Urticaria (n=3), injection site pain/swelling (n=2) arthralgia (n=1), weight gain (n=1)  4 (2.6%) in control (vehicle) group  Pruritus (n=2), injection site pain (n=1), urticaria (n=1)

17. 17 Common Adverse Events (Study 17P-CT-002) Preferred Term 17OHP N=310 n (%) Vehicle N=153 n (%) Injection site pain108 (34.8)50 (32.7) Injection site swelling53 (17.1)12 (7.8) Urticaria38 (12.3)17 (11.1) Pruritus24 (7.7)9 ( 5.9) Injection site pruritus18 (5.8)5 (3.3) Nausea18 (5.8)7 (4.6) Contusion17 (5.5)14 (9.2) Injection site nodule14 (4.5)3 (2.0) Vomiting10 (3.2)5 (3.3)

18. 18 Selected Pregnancy Complications (Studies 17P-CT-002 and 17P-IF-001) Pregnancy Complication Study 17OHPVehicle n (%)n Gestational Diabetes CT-00217(5.6)7(4.6) IF-0018(8.6)0(0.0) Oligohydramnios CT-00211(3.6)2(1.3) IF-0012(2.2)1(1.9) Preeclampsia CT-00227(8.8)7(4.6) IF-0016(6.5)2(3.8)

19. 19 Overview of Study 17P-IF-001 u Study Design  Double blind, vehicle controlled, randomized 2:1  Identical to that of Study 17P-CT-002 u Terminated prematurely: recall of study drug  150 subjects randomized before recall u 104 subjects completed treatment or withdrew for reasons other than recall of study drug  17OHP group: 65 subjects  Vehicle group: 39 subjects

20. 20 Key Findings from Study 17P-IF-001 Efficacy (Subjects not affected by recall) u Subjects with delivery < 37 weeks  17OHP – 43.1% (28 of 65)  Vehicle – 38.5% (15 of 39) Miscarriages, Stillbirths, and Neonatal Deaths Pregnancy Outcome 17OHP N=93 n (%) Vehicle N=54 n (%) Miscarriages (16 to <20 weeks)1(1.1)1(1.9) Stillbirths1(1.1)2(3.7) Neonatal Deaths2(2.2)0 Total Deaths4(4.4)3(5.9)

21. 21 Overview of Study 17P-FU Objective u Follow–up of children whose mothers were treated with either 17OHP or vehicle in the principal study Study Population u 14 of original 19 study sites eligible to participate (children from 374 of original 463 patients - 80%) u 278 of 374 (80%) of eligible children enrolled  17OHP: 194 children (82%)  Vehicle: 84 children (74%)

22. 22 Demographics of Children in Study 17P-FU u Mean Gestational Ages Study Gestational Age (Weeks) 17OHPVehicle 17P-CT-00236.235.2 17P-FU37.336.2 Months 17OHPVehicle Mean47.248.0 Range30.2, 63.933.5, 64.3 u Age at Evaluation in Study 17P FU

23. 23 Endpoints (Study 17P-FU) u Primary: Ages & Stages Questionnaire (ASQ)  Communication  Gross motor  Fine motor  Problem solving  Personal/social Positive Screen: score 2 S.D. below mean in any of 5 areas u Secondary: Survey Questionnaire  Activity/motor control  Vision/hearing  Height/weight/head circumference  Gender specific play  Diagnosis by a physician u Subjects also underwent physical exam

24. 24 Number (%) of Children with ASQ Scores Suggestive of Developmental Problem 17OHP N=193 Vehicle N=82 Area of Developmentn(%)n% Communication22(11.4)9(11.0) Gross Motor5(2.6)3(3.7) Fine Motor40(20.7)15(18.3) Problem Solving20(10.4)9(11.0) Personal-Social7(3.6)1(1.2) Developmental problem in one or more areas 53(27.5)23(28.0)

25. 25 Number (%) of Children with Low ASQ Score & Independent Diagnosis of Developmental Delay 17OHP (N=193) Vehicle (N=82) n (%)n Total Number Affected13(6.7)8(9.8) Area of Development Communication9(4.7)7(8.5) Gross Motor3(1.6)2(2.4) Fine Motor10(5.2)3(3.6) Problem Solving5(2.6)5(6.1) Personal-Social5(2.6)1(1.2)

26. 26 Summary of Issues u Applicant is seeking approval for 17OHP based on  Findings from a single clinical trial  A surrogate endpoint for infant mortality/morbidity (preterm birth < 37 weeks) u Concern about applicability to other populations  Preterm birth rate in vehicle arm that is higher than that reported in another MFMU Network trial u Safety concern  Potential safety signal of increased fetal wastage in 17OHP group