Meeting of the Advisory Committee for Reproductive Health Drugs August 29, 2006

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Meeting of the Advisory Committee for
Reproductive Health DrugsAugust 29, 2006

• Barbara Wesley, M.D., M.P.H.Division of
  Reproductive and Urologic Products

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NDA 21-945 17a Hydroxyprogesterone Caproate
(Gestiva)

• Proposed Indication
• Gestiva is indicated for the prevention of
  preterm birth in pregnant women with a history of
  at least one spontaneous preterm birth
• Dosage Administration
• Gestiva is to be administered IM at a dose of 250
  mg once a week beginning between 16-weeks 0-days
  (160 weeks) and 20-weeks 6-days (206 weeks)
  gestation to week 37 of gestation or birth

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Overview of Clinical Studies

• Study 17P-IF-001
• 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

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Study 17P-CT-002

• Design
• Double blind, vehicle-controlled with subjects
  randomized 21 to 17OHP or vehicle
• Inclusion Criteria
• History of spontaneous singleton preterm birth
• Gestational age of 160 to 206 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

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Study 17P-CT-002

• Study Medications
• 17a-hydroxyprogesterone caproate (250 mg/mL) in
  castor oil, benzyl benzoate, and benzyl alcohol
• Vehicle
• Dosing Regimen
• Weekly IM injection through Week 366 or delivery
• Primary Efficacy Endpoint
• Birth lt 370 weeks
• Additional Efficacy Endpoints (post hoc)
• Birth lt 350 weeks and lt 320 weeks
• Composite index of neonatal morbidity
• Death, RDS, bronchopulmonary dysplasia, Gr. 3 or
  4 IVH, proven sepsis, necrotizing enterocolitis

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Overview of Subject DispositionStudy 17P-CT-002
17OHP N310 n () Vehicle N153 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
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Preterm Births lt370 Weeks Gestation in ITT
Population (Study 17-P-CT-002)
Primary Efficacy Endpoint
17OHP N 310 Vehicle N 153 Difference Adjusted 95 Confidence Interval
Number () Preterm Births Number () Preterm Births Difference Adjusted 95 Confidence Interval
115 (37.1) 84 (54.9) -17.8 -28, -7

• PTB rate of 54.9 in vehicle arm considerably
  greater than rate in other MFMU Network studies
• PTB rate of 37.1 in 17OHP arm similar to PTB
  rate in control arms in another MFMU Network
  studies

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Percent of Preterm Births in Revised ITT
Population (Study 17-P-CT-002)
Age at Delivery (Weeks) 17OHP N310 Vehicle N153 Difference Adjusted 95 Confidence Interval
Age at Delivery (Weeks) Percent Delivered Percent Delivered Difference Adjusted 95 Confidence Interval
lt 370 37.1 54.9 -17.8 -28, -7.0
lt 350 21.3 30.7 -9.4 -18.7, -0.2
lt 320 11.9 19.6 -7.7 -15.5, 0.1
lt 280 9.4 10.5 -1.1 -7.4, 5.2

• 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).

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Proportion of Enrolled Subjects Continuing to be
Pregnant by Gestational Age
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Gestational Age (Weeks) at Delivery (Study
17P-CT-002)
17OHPN306 VehicleN153
Median 37.5 36.5
Mean 36.2 35.2
Min, Max 18.1, 41.5 20.3, 41.6
Difference between groups (mean) 1.0 week
95CI 0.3,1.5
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Birthweight (Study 17P-CT-002)
17OHP N301 Vehicle N151
Mean Weight (gm) 2760 2582
Gm Difference 95CI 178.2 -13, 290 178.2 -13, 290

Birthweight n () n ()
lt2500 gm 82 (27.2) 62 (41.1)
Difference 95CI -13.8 -23, -4.5 -13.8 -23, -4.5
lt1500 gm 26 (8.6) 21 (13.9)
Difference 95CI -5.3 -11.6, 1.1 -5.3 -11.6, 1.1
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Miscarriages, Stillbirths, and Neonatal Deaths
(Study 17P-CT-002)
Pregnancy Outcome 17OHP N306 n () Vehicle N153 n ()
Miscarriages (16 to lt20 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)

• No net survival benefit

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Days from Onset of Treatment to Fetal or
Neonatal Death
1.0
Proportion Surviving
17OHP Vehicle
0.8
100
50
150
Days to Fetal or Neonatal Death
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Literature Reports of Fetal Loss in Women Treated
with 17-hydroxyprogesterone Caproate
Study 17OHPn N Vehicle n N
LeVine (1964) 3/15 7/15
Shearman (1968) 5/27 5/23
Johnson (1975) 3/23 0/27
Yemini et al. (1985) 8/39 3/40

n Number of fetal losses N Number of subjects
in treatment group From Keirse MJ, Brit J
Obstet Gynecol 1990 97(2)149-54
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Composite Neonatal Morbidity (Study 17P-CT-002)
Morbidity 17OHPN295n () VehicleN151n ()
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.
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Maternal Safety Findings (Study 17P-CT-002)

• Adverse event (AE) data not collected in usual
  manner
• Subjects asked if had any symptoms related to
  study medication
• No maternal deaths
• 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
• 11 subjects discontinued because of an AE
• 7 (2.2) in 17OHP group
• Urticaria (n3), injection site pain/swelling
  (n2) arthralgia (n1), weight gain (n1)
• 4 (2.6) in control (vehicle) group
• Pruritus (n2), injection site pain (n1),
  urticaria (n1)

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Common Adverse Events (Study 17P-CT-002)
Preferred Term 17OHP N310n () VehicleN153n ()
Injection site pain 108 (34.8) 50 (32.7)
Injection site swelling 53 (17.1) 12 (7.8)
Urticaria 38 (12.3) 17 (11.1)
Pruritus 24 (7.7) 9 ( 5.9)
Injection site pruritus 18 (5.8) 5 (3.3)
Nausea 18 (5.8) 7 (4.6)
Contusion 17 (5.5) 14 (9.2)
Injection site nodule 14 (4.5) 3 (2.0)
Vomiting 10 (3.2) 5 (3.3)
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Selected Pregnancy Complications (Studies
17P-CT-002 and 17P-IF-001)
Pregnancy Complication Study 17OHP 17OHP Vehicle Vehicle
Pregnancy Complication Study n () n ()
Gestational Diabetes CT-002 17 (5.6) 7 (4.6)
Gestational Diabetes IF-001 8 (8.6) 0 (0.0)
Oligohydramnios CT-002 11 (3.6) 2 (1.3)
Oligohydramnios IF-001 2 (2.2) 1 (1.9)
Preeclampsia CT-002 27 (8.8) 7 (4.6)
Preeclampsia IF-001 6 (6.5) 2 (3.8)
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Overview of Study 17P-IF-001

• Study Design
• Double blind, vehicle controlled, randomized 21
• Identical to that of Study 17P-CT-002
• Terminated prematurely recall of study drug
• 150 subjects randomized before recall
• 104 subjects completed treatment or withdrew for
  reasons other than recall of study drug
• 17OHP group 65 subjects
• Vehicle group 39 subjects

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Key Findings from Study 17P-IF-001

• Efficacy (Subjects not affected by recall)
• Subjects with delivery lt 37 weeks
• 17OHP 43.1 (28 of 65)
• Vehicle 38.5 (15 of 39)
• Miscarriages, Stillbirths, and Neonatal Deaths

Pregnancy Outcome 17OHPN93 n () VehicleN54n ()
Miscarriages (16 to lt20 weeks) 1 (1.1) 1 (1.9)
Stillbirths 1 (1.1) 2 (3.7)
Neonatal Deaths 2 (2.2) 0
Total Deaths 4 (4.4) 3 (5.9)
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Overview of Study 17P-FU

• Objective
• Followup of children whose mothers were treated
  with either 17OHP or vehicle in the principal
  study
• Study Population
• 14 of original 19 study sites eligible to
  participate (children from 374 of original 463
  patients - 80)
• 278 of 374 (80) of eligible children enrolled
• 17OHP 194 children (82)
• Vehicle 84 children (74)

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Demographics of Children in Study 17P-FU

• Mean Gestational Ages

Study Gestational Age (Weeks) Gestational Age (Weeks)
Study 17OHP Vehicle
17P-CT-002 36.2 35.2
17P-FU 37.3 36.2

• Age at Evaluation in Study 17P FU

Months Months
17OHP Vehicle
Mean 47.2 48.0
Range 30.2, 63.9 33.5, 64.3
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Endpoints (Study 17P-FU)

• 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
• Secondary Survey Questionnaire
• Activity/motor control
• Vision/hearing
• Height/weight/head circumference
• Gender specific play
• Diagnosis by a physician
• Subjects also underwent physical exam

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Number () of Children with ASQ Scores Suggestive
of Developmental Problem
17OHP N193 17OHP N193 Vehicle N82 Vehicle N82
Area of Development n () n
Communication 22 ( 11.4) 9 (11.0)
Gross Motor 5 (2.6) 3 (3.7)
Fine Motor 40 (20.7) 15 (18.3)
Problem Solving 20 ( 10.4) 9 (11.0)
Personal-Social 7 (3.6) 1 (1.2)

Developmental problem in one or more areas 53 (27.5) 23 (28.0)
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Number () of Children with Low ASQ Score
Independent Diagnosis of Developmental Delay
17OHP (N193) 17OHP (N193) Vehicle (N82) Vehicle (N82)
n () n ()
Total Number Affected 13 (6.7) 8 (9.8)

Area of Development
Communication 9 (4.7) 7 (8.5)
Gross Motor 3 (1.6) 2 (2.4)
Fine Motor 10 (5.2) 3 (3.6)
Problem Solving 5 (2.6) 5 (6.1)
Personal-Social 5 (2.6) 1 (1.2)
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Summary of Issues

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