# Presentation: 611035

## 17 -Hydroxyprogesterone Caproate Injection, 250 mg/mLNDA 21-945

- Adeza Biomedical
- Advisory Committee Meeting
- Reproductive Health Drugs
- August 29, 2006

## Durlin E Hickok, MD, MPH

- Vice President, Medical Affairs
- Adeza Biomedical

## Presentation

- Adeza Biomedical
- Medical Need
- Clinical Review
- Efficacy
- Safety
- Benefit / Risk

## Presenters

- Durlin E Hickok, MD, MPHVice President, Medical AffairsAdeza Biomedical
- Michael P. Nageotte, MDProfessor, Obstetrics and GynecologyUniversity of California, Irvine

## External Experts

| Paul J Meis, MD | Professor of Obstetrics and Gynecology
Wake Forest University  |
| --- | --- |
| Gwendolyn Norman, RN, MPH | Perinatal Research Nurse Coordinator 
Wayne State University |
| Michael O’Shea, MD, MPH | Professor of Pediatrics
Wake Forest University |
| Melissa Parisi, MD, PhD | Assistant Professor of Pediatrics 
University of Washington |
| David A Savitz, PhD | Professor of Community and Preventive Medicine 
Mount Sinai School of Medicine |
| Frank Stanczyk, PhD | Professor of Obstetrics and Gynecology
University of Southern California |

## Adeza Biomedical

- Medical technology company
- Focused on pregnancy-related and female reproductive disorders
- preterm birth
- infertility
- Submitted NDA for FDA approval to market 17P in the US for the prevention of recurrent preterm birth

## Nomenclature

- 17-HPC
- 17 α-hydroxyprogesterone caproate
- 17P
- Clinical study formulation of 17-HPC for injectionused in the NICHD Study
- GestivaTM
- Adeza’s proposed trade name for 17P
- Delalutin®
- Trade name of previously marketed 17-HPC

## 17-HPC

**17-HPC**

- 17 -hydroxyprogesterone caproate
- The active pharmaceutical ingredient of 17P
- An esterified derivative of the naturally occurring 17 -hydroxyprogesterone
- Substantial progestational activity
- Prolonged duration of action

## 17P

- 17P is a sterile solution for injection containing:
- 17-HPC (250 mg/mL)
- Castor oil USP
- Benzyl benzoate USP
- Benzyl alcohol NF
- Used in NICHD clinical studies
- Identical in composition to previously marketed Delalutin

## 17-HPC – History

- Delalutin approved by FDA in 1956
- Indications
- treatment of habitual and recurrent miscarriage
- threatened miscarriage
- postpartum after pains
- advanced uterine cancer
- Voluntarily withdrawn from US market in 1999 for reasons not related to safety or effectiveness
- Multiple studies evaluated safety and efficacy of 17-HPC for prevention of preterm birth

## 17-HPC Studies for Preterm Birth 

## 17-HPC Studies for Preterm Birth (continued)

## 17-HPC Studies for Preterm Birth – Forest Plot

## Development of 17P NDA Submission

- NICHD conducted controlled clinical study evaluating 17P for prevention of recurrent preterm birth
- Results published in *New England Journal of Medicine*, 2003
- Adeza allowed access to clinical database

## Development of 17P NDA Submission

- Results from NICHD study provide primary basis for efficacy claim of Adeza’s NDA submission for 17P
- Large, multicenter study
- Highly statistically significant efficacy findings
- Study stopped early by DSMC for efficacy
- Results consistent across subsets of patients

## Proposed Indication for Gestiva (17P)

- 	“Gestiva is indicated for the prevention of preterm birth in pregnant women with a history of at least one spontaneous preterm birth.”

## Medical Need

- Michael P Nageotte, MD
- Professor, Obstetrics & Gynecology
- University of California, Irvine
- Immediate Past President
- Society for Maternal-Fetal Medicine

## Definition of Preterm Birth

- Preterm birth is defined as birth before the 37th week of gestation

## Preterm Birth in the US

- Incidence of preterm birth continues to risea
- Costs exceed $26 billion annually
- One preterm birth occurs every minute in the US
- March of Dimes launched a multimillion dollar campaign to reduce preterm births
- Reduction in preterm births will alleviate primary cause of perinatal and neonatal morbidity and mortalityb

**33% increase since 1981**

- aHamilton BE et al. *Natl Vital Stat Rep*. 54(8):1-17; 2005
- bSpong CY. *Obstet Gynecol*. 101(6):1153-4; 2003** **

## Morbidities Associated with Preterm Birth

- Respiratory distress syndrome (RDS)
- Intraventricular hemorrhage (IVH)
- Periventricular leukomalacia (PVL)
- Necrotizing enterocolitis (NEC)
- Apnea
- Jaundice
- Anemia
- Infections due to immature immune systems
- Neonatal death

## Neonatal Long-Term Morbidities

- Potential long-term outcomes
- Retinopathy
- Cerebral palsy
- Mental retardation
- Learning disabilities
- Attention deficit disorders

## Risk Factors for Preterm Birth

- From: Goldenberg RL et al. *Am J Public Health.* 88:233-238; 1998

## Benefits of Prolonging Pregnancy – Mortality

- Improved survival with gestational age

- From: St. John EB et al. *J Obstet Gynecol.* 182:170-175; 2000

## Benefits of Prolonging Pregnancy – Length of Stay

- Reduced neonatal hospital days

- From: Gilbert WM et al. *Obstet Gynecol.* 102:488-492; 2003

## Significance of Late Preterm Birth

- Contributes substantially to overall preterm births
- 58% between 35-36 weeks
- 79% greater than 32 weeks

- From: March of Dimes, 2006

## Significance of Late Preterm Birth

- Increased mortalitya
- Mortality risk approximately 3-fold higher at 35-36 weeks
- Increased morbiditiesb,c
- Respiratory distress requiring O2
- Temperature instability
- Hypoglycemia
- Jaundice
- Attention deficit disorders
- Increased hospitalizations and associated costsb,c
- Initial hospitalization costs approximately 3-fold higher
- Risk for rehospitalization from 2 weeks to 6 months post discharge increased

- aKramer MS et al. *JAMA*. 284:843-9; 2000** **
- bWang ML et al. *Pediatrics*. 114:372-6; 2004
- cEscobar GJ et al. *Semin Perinatol*. 30(1):28-33; 2006

## Available Treatments

- Treatment of preterm labor
- Tocolytics effective for short-term prolongation after onset of labor
- Prevention of preterm birth
- No effective treatments identified prior to 17P
- American College of Obstetricians and Gynecologists (ACOG) recommends use to prevent recurrent preterm birth in 2003 after publication of the NICHD studya,b
- 17P currently in use among Ob/Gyn community for prevention of recurrent preterm birth

- aACOG News Release, 2003
- bACOG Committee Opinion. *Obstet Gynecol*. 102(5 pt 1):1115-6; 2003**  **

## Current Availability of 17P

- Available only from compounding pharmacies
- No consistent labeling/prescribing information
- Limited FDA oversight
- No regulations ensuring consistency of products between compounding pharmacies
- No federal regulations requiring reporting of AE/SAEs (MedWatch)

## Conclusions

- Compelling need to address rising incidence of preterm birth and associated costs and morbidities
- Benefits of prolonging pregnancy at any gestation
- Prevention of early preterm births
- Prevention of late preterm births
- Need for FDA-approved product

## Clinical Review

## National Institute of Child Health and Human Development (NICHD)

- Part of the National Institutes of Health (NIH)
- Objectives
- Identify causes of prematurity
- Evaluate safety and effectiveness of treatments
- Maternal-Fetal Medicine Units (MFMU) Network
- Consists of major medical training institutions
- Engages in multicenter collaborative investigations

## NICHD MFMU Network Sites for 17P Study

- University of Pittsburgh
- University of Tennessee
- University of Alabama
- Wayne State University
- University of Cincinnati
- Wake Forest University
- University of Chicago
- Ohio State University
- University of Miami
- University of Texas Southwestern

- University of Texas San Antonio
- University of Utah
- Thomas Jefferson University
- Brown University
- Columbia University
- Case Western University
- University of Texas Houston
- University of North Carolina
- Northwestern University

## Overview of NICHD Clinical Studies

- Study 002
- Initiated in 1999, completed in 2002
- Randomized, placebo-controlled, double-blind, multi-center clinical study
- Weekly IM injections from 160 and 206 weeks of gestation until 366 weeks gestation or birth
- Enrolled 463 patients in 2:1 ratio active to placebo
- DSMC recommended study be halted early
- Interim analysis conducted on 351 completed patients
- Boundary for test of significance had been crossed
- Indicated a benefit for 17P in reducing preterm birth
- Results form primary basis for efficacy

## Overview of NICHD Clinical Studies

- Study 001
- Initiated in 1998
- Terminated due to manufacturer and FDA recall of study drug
- Enrolled only 150 of 500 planned patients

## Overview of NICHD Clinical Studies

- Follow-Up Study
- Observational follow-up safety study to assess the long term safety outcome of infants exposed to 17P in utero
- Examined health and development of infants born during Study 002
- Conducted at 15 MFMU Network study centers
- Enrolled 278 children

## Efficacy and Safety Databases

- Efficacy Assessment
- Study 002
- Safety Assessment
- Study 002
- Study 001
- Follow-Up Study

## Efficacy

## Enrollment Criteria

- Pregnant women with documented history of previous singleton spontaneous preterm delivery (SPTD)
- Gestational age of 160 to 206  weeks at randomization
- Exclusion criteria:
- Multifetal gestation
- Known major fetal anomaly or fetal demise
- Prior progesterone treatment during current pregnancy
- Prior heparin therapy during current pregnancy
- History of thromboembolic disease
- History of maternal medical/obstetrical complications (eg current or planned cerclage, HTN requiring medications, seizure disorder)

## Patient Enrollment – Study 002

- Total of 463 patients
- 2:1 randomization (active:placebo)
- 310 in 17P group
- 153 in Placebo group
- 418 (90.3%) patients completed injections through 366 weeks gestation or birth
- 279 (90.0%) in 17P group
- 139 (90.8%) in Placebo group

## Baseline Demographics

| Characteristic | 17P
(N=310) | Placebo
(N=153) | P value |
| --- | --- | --- | --- |
| Age, yr mean (SD) | 26.0 (5.6) | 26.5 (5.4) | 	0.2481 |
| Race or ethnic group |  |  | 	0.8736 |
| 	African American | 	59.0% | 	58.8% |  |
| 	Caucasian | 	25.5% | 	22.2% |  |
| 	Hispanic | 	13.9% | 	17.0% |  |
| 	Asian | 	0.6% | 	0.7% |  |
| 	Other | 	1.0% | 	1.3% |  |
| Marital status |  |  | 	0.6076 |
| 	Married or living with partner | 	51.3% | 	46.4% |  |
| 	Divorced, widowed or separated | 	10.3% | 	11.8% |  |
| 	Never married | 	38.4% | 	41.8% |  |
| Years of education, mean (SD) | 11.7 (2.3) | 11.9 (2.3) | 	0.2175 |

## Baseline Pregnancy Characteristics 

| Characteristic | 17P
(N=310) | Placebo
(N=153) | P value |
| --- | --- | --- | --- |
| Body mass index (kg/m2), mean (SD) | 26.9 (7.9) | 26.0 (7.0) | 	0.3310 |
| Diabetes | 	4.2% | 	2.6% | 	0.3954 |
| Smoked cigarettes during pregnancy | 	22.6% | 	19.6% | 	0.4647 |
| Alcoholic drinks during pregnancy | 	8.7% | 	6.5% | 	0.4172 |
| Used street drugs during pregnancy | 	3.5% | 	2.6% | 	0.7822 |
| Duration of gestation at randomization (wk), mean (SD) | 	18.9 (1.4) | 	18.8 (1.5) | 	0.5929 |

## Previous Obstetrical History

| Obstetrical History | 17P
(N=310) | Placebo
(N=153) | P value |
| --- | --- | --- | --- |
| Number previous SPTD, mean (SD)  | 	1.3 (0.7) | 	1.5 (0.9) | 	0.0017 |
| >1 Previous PTB | 	27.7% | 	41.2% | 	0.0036 |
| Gestational age qualifying delivery (wk), mean (SD) | 	30.6 (4.6) | 	31.3 (4.2) | 	0.2078 |
| Previous miscarriage | 	30.0% | 	37.3% | 	0.1166 |

## Efficacy Endpoints – Primary

- Preterm birth <37 weeks

## Primary Efficacy Results Preterm Birth <37 Weeks

|  | 17P | Placebo |  |
| --- | --- | --- | --- |
| Population | N (%) | N (%) | P value |
| Intent-to-treat | 	310 (37.1) | 	153 (54.9) | 	0.0003 |
|  |  |  | 	0.0010a |
| All available datab | 	306 (36.3) | 	153 (54.9) | 	0.0001 |
|  |  |  | 	0.0006a |
| aP value from a logistic regression adjusting for the number of previous preterm deliveries
bAnalysis population represents that reported by Meis et al (2003) and excludes 4 patients lost to follow-up |  |  |  |

**Primary Efficacy Results ****Preterm Birth <37 Weeks**

## Preterm Birth <37 Weeks of Gestation 

- Breslow-Day P value >0.05

***Number of Previous Preterm Births***

## Preterm Birth <37 Weeks of Gestation

***Race***

- Breslow-Day P value >0.05

## Preterm Birth <37 Weeks of Gestation

***Bacterial Vaginosis***

- Breslow-Day P value >0.05

## Preterm Birth <37 Weeks of Gestation 

***Gestational Age of Qualifying Preterm Birth***

- Breslow-Day P value >0.05

## Secondary Maternal Efficacy Endpoint Results

| Pregnancy Outcome | 17P
(N=310)
% | Placebo
(N=153)
% | P value |
| --- | --- | --- | --- |
| Preterm birth <350  weeks | 	21.3 | 	30.7 | 0.0263 |
| Preterm birth <320  weeks | 	11.9 | 	19.6 | 0.0273 |
| Preterm birth <300  weeks | 9.7 | 	15.7 | 0.0581 |

**Secondary Maternal ****Efficacy Endpoint Results**

- Note: Data from the 4 patients lost to follow-up are included based upon last known date pregnant

## Preterm Birth <37, <35, <32, and <30 Weeks

**↓ ****30.6%**

**↓ ****32.4%**

**↓ ****39.3%**

**↓ ****38.2%**

- Note: Data from the 4 patients lost to follow-up are included based upon last known date pregnant

## Gestational Ages at Birth

| Gestational Age at Birth | 17P 
(N=310)
% | Placebo (N=153)
% |
| --- | --- | --- |
| Term (>37 weeks) | 	62.9 | 	45.1 |
| 350-366 weeks | 	15.8 | 	24.2 |
| 320-346 weeks | 	9.4 | 	11.1 |
| 280-316 weeks | 	2.6 | 	9.2 |
| 240-276 weeks | 	3.9 | 	7.2 |
| 200-236 weeks | 	3.6 | 	3.3 |
| 160-196 weeks | 	1.9 | 	0 |
| Total | 100% | 100% |

## Hazard Ratio for Delivery

| Gestational Age at Delivery | Hazard 
Ratio | 95% Confidence Interval |
| --- | --- | --- |
| Term (>37 weeks) | 1.00 | –  |
| 350-366 weeks | 0.52 | 0.28 – 0.94 |
| 320-346 weeks | 0.73 | 0.31 – 1.70 |
| 280-316 weeks | 0.27 | 0.08 – 0.90 |
| 240-276 weeks | 0.54 | 0.17 – 1.72 |
| 200-236 weeks | 1.01 | 0.23 – 4.50 |
| 160-196 weeks | NC | NC |

- NC=not calculable

## Neonatal Outcomes

| Neonatal Outcome | 17P | Placebo | P value |
| --- | --- | --- | --- |
| Birthweight  |  |  |  |
| 	<2500 g  | 	27.2% | 	41.1% | 	0.0029 |
| 	<1500 g | 	8.6% | 	13.9% | 	0.0834 |
| Birthweight (g), mean (SD) | 2760 (859) | 2582 (942) | 	0.0736 |
| Admitted to NICU (live births) | 	27.8% | 	36.4% | 	0.0434 |
| Days in NICU (median) | 	9.1 | 	14.1 | 	0.1283 |

## Neonatal Morbidities

| Neonatal Morbidity | 17P | Placebo | P value |
| --- | --- | --- | --- |
| Necrotizing enterocolitis (NEC) | 	0% | 	2.7% | 	0.0127 |
| Intraventricular hemorrhage (IVH) | 	1.4% | 	5.3% | 	0.0258 |
| Supplemental oxygen | 	15.4% | 	24.2% | 	0.0248 |
| Days respiratory therapy (mean) | 	1.7 | 	2.7 | 	0.0438 |
| Ventilator support | 	8.9% | 	14.8% | 	0.0616 |
| Transient tachypnea | 	3.7% | 	7.3% | 	0.0990 |
| Respiratory distress syndrome (RDS) | 	9.9% | 	15.3% | 	0.0900 |
| Bronchopulmonary dysplasia (BPD) | 	1.4% | 	3.3% | 	0.1730 |
| Patent ductus arteriosis (PDA) | 	2.4% | 	5.4% | 	0.1004 |

## Composite Neonatal Morbidity Index

- Conducted as post hoc analysis
- Defined as any liveborn infant who experienced one or more of the following:
- Death
- Respiratory distress syndrome (RDS)
- Bronchopulmonary dysplasia (BPD)
- Grade 3 or 4 intraventricular hemorrhage (IVH)
- Proven sepsis
- Necrotizing enterocolitis (NEC)
- Trend toward improvement with 17P
- 11.9% in 17P group
- 17.2% in Placebo group

## Summary of NICHD Efficacy Results 

- Weekly administration of 17P
- Reduces rate of recurrent preterm birth at <37, <35, and <32 weeks
- prolongs gestation
- consistent with previous studies
- Improves neonatal outcomes
- reduced percentage of infants born <2500 g
- reduced admission rate to NICU
- Reduces specific neonatal morbidities
- NEC, IVH, supplemental oxygen, mean days of respiratory therapy

## Safety 

## Safety Database

- Study 002
- Study 001
- Follow-Up Study

## Safety Database Exposure –Studies 002 and 001

- 613 Patients exposed to at least 1 injection
- 17P 		 	404 patients
- Placebo		209 patients

## Pregnancy Related Admissions/Procedures 

|  | 17P
(N=399)% | Placebo
(N=205)% | P value |
| --- | --- | --- | --- |
| Hospital or labor admission for preterm labor | 	14.8 | 	15.6 | 	0.7834 |
| Cerclage placement | 	1.3 | 	1.5 | 	1.0000 |

## Pregnancy Related Complications  

| Complication | 17P
(N=399)
% | Placebo
(N=205)
% | P value |
| --- | --- | --- | --- |
| Preeclampsia or gestational hypertension | 	8.3 | 	4.4 | 	0.0795 |
| Gestational diabetes | 	6.3 | 	3.4 | 	0.1792 |
| Oligohydramnios | 	3.3 | 	1.5 | 	0.2851 |
| Abruption | 	1.8 | 	2.9 | 	0.3565 |
| Significant antepartum bleeding | 	2.5 | 	3.4 | 	0.5654 |
| Clinical chorioamnionitis | 	3.3 | 	2.4 | 	0.8011 |
| Other complication | 	2.6 | 	3.0 | 	0.7928 |

## Most Frequently Reported Maternal Adverse Events

|  | 17P
(N=404)
% | Placebo
(N=209)
% |
| --- | --- | --- |
| Any adverse event (AE) | 	59.2 | 	56.5 |
| Preferred Term |  | 	 |
| 	Injection site reactions | 	44.6 | 	40.7 |
| 	Urticaria | 	12.6 | 	11.5 |
| 	Pruritus  | 	6.9 | 	5.3 |
| 	Contusion | 	6.4 | 	9.6 |
| 	Nausea | 	5.0 | 	3.8 |
|  |  |  |

- Note: Table presents those adverse events reported by at least 2% of patients in either treatment group

## Discontinuations Due to Adverse Events

- Patients discontinued early due to AEs
- 17P group – 2.2% patients
- Placebo group – 3.3% patients
- Injection site reactions most common
- 17P group – 1.0% patients
- Placebo group – 1.4% patients

## Serious Adverse Events

- SAEs collected according to NICHD standardized procedures
- All deaths (maternal, neonatal, fetal)
- Other serious and unexpected AEs
- Analysis also included congenital anomalies

## Serious Adverse Events – Nonfatal

|  | 17P
(N=404)
% | Placebo
(N=209)
% |
| --- | --- | --- |
| Any SAEs (Total) | 	9.4 | 	10.5 |
| 	Nonfatal SAEs | 	 |  |
| 		Congenital anomalies | 	2.2 | 	1.9 |
| 		Injection site reactions | 	1.0 | 	1.0 |
| 			Hypersensitivity/adverse drug reaction | 	0.2 | 	0.5 |
| 		Infection | 	0.5 | 	0 |
| 		Pulmonary embolism (maternal) | 	0.2 | 	0 |
| 		Uterine rupture | 	0.2 | 	0 |
| 		Pruritus | 	0 | 	0.5 |
| 		Arthralgia | 	0.2 | 	0 |
| 		Testicular infarction | 	0.2 | 	0 |

## Congenital Anomalies Assessed at Birth

|  | 17P
(N=404)
% | Placebo
(N=209)
% |
| --- | --- | --- |
| Congenital anomalies | 	2.2 | 	1.9 |
| 	Musculoskeletal | 	0.7 | 	1.0 |
| 	Cardiovascular | 	0.5 | 	0.5 |
| 	Genitourinary | 	0.2 | 	0.5 |
| 	Male reproductive | 	0.5 | 	0.5 |
| 	Breast | 	0.2 | 	0 |

## 

No neonatal deaths, stillbirths, or miscarriages were considered related to study drug by investigators

- No neonatal deaths, stillbirths, or miscarriages were considered related to study drug by investigators

|  | 17P
(N=404)
% | Placebo
(N=209)
% | P value |
| --- | --- | --- | --- |
| Miscarriages | 	1.5 | 	0.5 | 0.2629 |
| Stillbirths | 	1.7 | 	1.9 | 0.8769 |
| Neonatal deaths | 	2.5 | 	4.3 | 0.1928 |

**Serious Adverse Events – Fetal/Neonatal Deaths**

## Summary of Miscarriage Rates (16-20 Weeks) – NICHD Network Studies

## 17-HPC for Prevention of Miscarriage – Cochrane Database Review  (2003)

- No difference between 17-HPC and Placebo
- OR = 0.77 [0.36 – 1.68]
- Significant protective effect for progestins in women with ≥ 3 prior miscarriages
- OR = 0.39 [0.17 - 0.91]
- 3 studies, 1 of which used 17-HPC
- No difference for adverse effects on infant or mother

- Oates-Whitehead RM et al.* Cochrane* *Database Syst Rev*. (4):CD003511; 2003

## Safety Conclusions – Studies 002 and 001

- The safety results demonstrate that weekly administration of 17P was
- Safe and well tolerated by pregnant women
- Safe for the developing fetus and neonate
- Comparable rates of stillbirths, miscarriages, and neonatal deaths
- Rates of congenital anomalies similar to general population rate of 2-3%

## 17P Follow-Up Study

- Assessed long-term impact of in utero exposure to 17P
- Observational safety study
- Based on surveys and physical examinations
- Enrolled 278 children born to women enrolled in Study 002
- 17P Group – 194 infants (68% of births)
- Placebo Group – 84 infants (59% of births)
- Age range from 30-64 months

## Demographics Follow-Up Study

|  | 17P
(N=194) | Placebo
(N=84) |
| --- | --- | --- |
| Age at enrollment (mo), mean (SD) | 47.2 (8.6) | 48.0 (8.3) |
| Gestational age at birth (wk), mean (SD) | 37.3 (3.2) | 36.2 (3.7) |
| Race/Ethnicity |  |  |
| 	African American | 	54.1% | 	56.0% |
| 	Caucasian | 	28.4% | 	23.8% |
| 	Hispanic | 	14.9% | 	17.9% |
| 	Asian | 	1.0% | 	1.2% |
| Sex | 	 |  |
| 	Male | 	58.2% | 	47.6% |
| 	Female | 	41.8% | 	52.4% |

## 17P Follow-Up Study Components

- Based on surveys and physical examination
- Ages and Stages Questionnaire
- Survey Questionnaire
- Physical Examination

## Child Safety Assessments Follow-Up Study

- Ages and Stages Questionnaire (ASQ)
- Widely used and validated screening tool
- Identifies children at risk for developmental delay
- Communication
- Gross motor movement
- Fine motor movement
- Problem-solving
- Personal-social

## ASQ Sample Questions3 Yr Old – Sample Questions

- Communication – ‘Does your child make sentences that are three or four words long?’
- Gross motor – ‘Does your child jump with both feet leaving the floor at the same time?’
- Fine motor – ‘Does your child thread a shoelace through either a bead or an eyelet of a shoe?’
- Problem-solving – ‘If your child wants something he cannot reach, does he find a chair or box to stand on to reach it?’
- Personal-social – ‘Can your child put on a coat, jacket or shirt by himself?’
- Overall – ‘Does anything about your child worry you?’
- Response options:
- Yes
- Sometimes
- Not yet

## ASQ Results

| Area of Development | 17P
(N=193)
% | Placebo
(N=82)
% | P value |
| --- | --- | --- | --- |
| Occurrence of score below cutoff on ≥1 area of development | 	27.5 | 	28.0 | 	0.9206 |
| 	Communication | 	11.4 | 	11.0 | 	0.9191 |
| 	Gross Motor | 	2.6 | 	3.7 | 	0.6989 |
| 	Fine Motor | 	20.7 | 	18.3 | 	0.6445 |
| 	Problem Solving | 	10.4 | 	11.0 | 	0.8797 |
| 	Personal-Social | 	3.6 | 	1.2 | 	0.4427 |

- Conclusion: No differences observed between 17P and placebo

## Child Safety Assessments Follow-Up Study

- Survey Questionnaire derived from
- Preschool Activities Inventory
- 2001 Child Health Supplement of the National Health Interview Survey
- 1991 National Maternal and Infant Health Survey
- Early Childhood Longitudinal Survey (Department of Education)
- Avon Longitudinal Study of Parents and Children

## Survey QuestionnaireSample Questions

- Communication/Problem Solving
- ‘Does (name) pronounce words, communicate with and understand others?’
- Motor Skills/Activity Level
- ‘Do you have any concerns about (name)’s overall activity level?’
- Overall Health
- ‘Does (name) have an impairment or health problem that limits his/her ability to walk, run or play?’
- Personal-Social
- ‘How often in the past month has he/she done the following?: played house, played ball games, played at fighting, played at being a mother or father, etc.’

## Survey Questionnaire

- Survey Questionnaire results revealed no significant differences in
- Physical growth
- Motor skills/activity levels
- Communication and problem solving
- Overall health
- Reported diagnoses by health professionals
- Hearing, vision, and use of special equipment
- Gender-specific play

## Physical Examination

- General examination of body systems
- Documentation of any major abnormalities
- Specific identification of genital anomalies

## Physical Examination Findings

| Abnormality or Location of Abnormality | 17P
(N=194)
% | Placebo
(N=84)
% |
| --- | --- | --- |
| Skin | 	12.3 | 	7.5 |
| Inguinal nodes palpable | 	10.9 | 	8.8 |
| Mouth | 	9.1 | 	8.6 |
| Neck | 	5.9 | 	4.9 |
| Heart | 	5.3 | 	0 |
| Ears | 	3.2 | 	3.7 |
| Supraclavicular nodes palpable | 	3.3 | 	2.5 |
| Other syndromes or stigmata | 	2.7 | 	5.1 |

## Safety – Literature Review

- Epidemiological studies
- Michaelis, West Germany (1983)
- n = 462
- Resseguie, Mayo Clinic (1985)
- n = 649, 11.5 year mean follow-up
- Katz, Israel (1985)
- n = 1,608
- No association between 17-HPC exposure and congenital anomalies

## FDA Assessment on Progestogen Class

- Background to the 1999 ruling noted
*	**“**The reliable evidence, particularly from controlled studies, shows no increase in congenital anomalies, including genital abnormalities in male or female infants, from exposure during pregnancy to progesterone or hydroxyprogesterone.”*

- From: FDA. 64 FR:17985 – 17988. April 13, 1999

## Overall Safety Conclusions – NICHD Studies and Literature Review

- 17P considered safe based on:
-  NICHD studies
- Safe and well tolerated in pregnant women
- Safe for the developing fetus and neonate based on
- Comparable percentage of surviving offspring
- Rates of congenital anomalies similar to general population rates of 2-3%
- Safe for the child as evidenced by the lack of untoward effects on developmental milestones or physical health on follow-up safety assessments
- Literature review
- FDA assessment on progestogen class

## Benefit / Risk

- Preterm birth is major unmet medical need
- Leading cause of perinatal and neonatal mortality and morbidity
- 33% increase in incidence of preterm birth since 1981
- $26 billion annual cost associated with treating preterm infants
- Staggering financial, social, and emotional costs associated with both early and late preterm birth

## Benefit / Risk

- 17P has been shown to reduce the incidence of preterm birth
- Significant efficacy demonstrated <37, <35, and <32 weeks of gestation
- 32% reduction at <37 weeks
- 31% reduction at <35 weeks
- 39% reduction at <32 weeks
- Results applicable irrespective of
- Race of the mother
- Number of previous preterm births
- Gestational age of previous preterm birth

## Benefit / Risk

- 17P treatment leads to healthier neonates
- Lengthens mean gestational age at birth
- Results in fewer infants under 2500 grams
- 34% reduction
- Reduces admissions to NICU
- 24% reduction
- Reduces important neonatal morbidities
- Respiratory therapy
- Necrotizing enterocolitis
- Intraventricular hemorrhage

## Benefit / Risk

- 17P administration was safe for pregnant women
- Well tolerated
- No increase in rates of complications or procedures
- No identified risk for fetus and neonate
- Comparable rates of neonatal deaths, miscarriages, and stillbirths
- No evidence of teratogenicity
- Congenital anomalies at similar rates
- Confirmed by 1999 FDA assessment
- Second trimester administration
- No identified risk for the child
- No association with developmental delays or other issues in children between 30 and 64 months of age

## Proposed Indication

- 	“Gestiva is indicated for the prevention of preterm birth in pregnant women with a history of at least one spontaneous preterm birth.”

## All Back Up Slides Presented During Q&A

- Not in any specific order

## Hochberg* Adjustment for Multiple Comparisons

| Outcome | P value | Rank | Statistically significant | Adjusted P value |
| --- | --- | --- | --- | --- |
| PTD <32 | 	0.027 | 1 | Yes | 0.027 |
| PTD <35 | 	0.026 | 2 | Yes | 0.027 |
| PTD <37 | 	0.0003 | 3 | Yes | 0.0009 |
| *Hochberg Y., Biometrica (1988) |  |  |  |  |

## Development of the External Genitalia (2 of 2)

- The Developing Human: Clinically Oriented Embryology, Moore, Persaud 2003

## Development of the External Genitalia (1 of 2)

- The Developing Human: Clinically Oriented Embryology, Moore, Persaud 2003

## Unlike Progesterone, 17-HPC Is Not Converted to Androgens, Estrogens or Corticosteroids

## Bacterial Vaginosis During Pregnancy vs Outcome

|  | 17P
N=64 | Placebo
N=24 |
| --- | --- | --- |
| Miscarriage | 1 (1.6%) | 0 (0%) |
| Stillborn | 2 (3.1%) | 1 (4.2%) |
| pPROM <37 | 6 (9.4%) | 7 (29.2%) |
| Neonatal Sepsisa | 2 (3.3%) | 0 (0%) |
| Cerebral palsyb | 0/46 (0) | 0/16 (0) |

**a ****based on livebirths**
**b**** Based on 62 children enrolled in the Follow-up Study **

## Preterm Birth <37 in Patients with Bacterial Vaginosis

|  | 17Pn/N (%) | Placebon/N (%) |
| --- | --- | --- |
| Preterm birth <37 weeks |  |  |
| No bacterial vaginosis | 88/246 (35.8) | 67/129 (51.9) |
| Bacterial vaginosis | 27/64 (42.2) | 17/24 (70.8) |

## Reasons for Oral Metronidazole Use

|  | 17P
(N=32)
n % | Placebo
(N=8)
n % |
| --- | --- | --- |
| Bacterial vaginosis | 25 (78.1) | 6 (75.0) |
| Trichomonas | 10 (31.3) | 2 (25.0) |
| Other vaginal/cervical infection | 0 (0) | 1 (12.5) |

**Reasons for Oral Metronidazole Use**

**Note: 2 patients in the 17P group and 1 patient in the placebo group had**
**both bacterial vaginosis and trichomonas**

## Use of Metronidazole

|  | 17P
(N=310)
n % | Placebo
(N=153)
n % |
| --- | --- | --- |
| Oral | 32 (10.3) | 8 (5.2) |
| Vaginal | 1 (0.3) | 1 (0.7) |
| Any use | 33 (10.7) | 9 (5.9) |

**Use of Metronidazole**

## Incidence of BV

|  | 17P
(N=310)
n % | Placebo
(N=153)
n % |
| --- | --- | --- |
| Prior to randomization | 41 (13.2) | 	20 (13.1) |
| Randomization through delivery | 27 (8.7) | 8 (5.2) |
| At any time during pregnancy | 64 (20.7) | 24 (15.7) |

**Incidence of BV**

**Note: 4 patients in each group has BV prior to randomization and from **
**randomization through delivery**

## Chorioamnionitis at Delivery 

|  | 17PN=399n (%) | PlaceboN=205n (%) | P value |
| --- | --- | --- | --- |
| 
Confirmed clinical chorioamnionitis
 | 13 (3.3) | 5 (2.4) | 0.8011 |

## Infections – BV and Trichomonas

- Collected on CRF at 2 time points:
- At baseline, patient report and record review
- During study, the CRF for “Record of Antibiotic Use” included the reason for administration of antibiotic
- Clinical chorioamnionitis
- Collected on the labor and delivery summary CRF
- Diagnosed by treating physician based on methods and criteria based at the local site

## Gestational Diabetes – Summary

- Gestational diabetes following randomization was not statistically different (P=0.179)
- 17P = 6.3%
- Placebo = 3.4%
- Gestational diabetes rate reported by the  American Diabetes Association ~ 7%
- Progestins may disturb glucose homeostasis
- Rates of gestational diabetes in this study were similar to ADA

## Gestational Diabetes – Integrated Studies

|  | 17P
n/N* (%) | Placebo
n/N* (%) |
| --- | --- | --- |
| No history of diabetes | 25/382 (6.5) | 7/200 (3.5) |

**Gestational Diabetes – Integrated Studies**

**Rate of Gestational Diabetes**

***Number of women without a history of diabetes at baseline**

## Diabetes – Study 001 

|  | 17P
n/N* (%) | Placebo
n/N* (%) |
| --- | --- | --- |
| No history of diabetes | 	8/89 (9.0) | 	0/52 (0) |

**Diabetes – Study 001 **

**Rate of Gestational Diabetes**

***Number of women without a history of diabetes at baseline**

## Diabetes Study 002

|  | 17P
n/N* (%) | Placebo
n/N* (%) |
| --- | --- | --- |
| No history of diabetes | 	17/293 (5.8) | 	7/148 (4.7) |

**Diabetes Study 002**

**Rate of Gestational Diabetes**

***Number of women without a history of diabetes at baseline**

## Prevention of Preterm Birth Integrated Results

| Pregnancy Outcome | 17P
(N=404)
% | Placebo
(N=209)
% | P value |
| --- | --- | --- | --- |
| Birth <370  weeks
 | 38.1
 | 49.8
 | 0.0052
0.0155a |
| Birth <350 weeks | 22.0 | 30.6 | 0.0211 |
| Birth <320  weeks | 12.4 | 18.7 | 0.0367 |
| aP value from a logistic regression adjusting for the number of previous preterm deliveries |  |  |  |

**Prevention of Preterm Birth ****Integrated Results**

## Composition of Injectable Formulations of 17-HPC 

| Component | Adeza Product | Study 17P-CT-002 | Delalutin, 250 mg/mL |
| --- | --- | --- | --- |
| 17-HPC | 250 mg/mL | 250 mg/mL | 250 mg/mL |
| Benzyl benzoate | 46% | 46% | 46% |
| Benzyl alcohol | 2% | 2% | 2% |
| Castor oil | q.s. to volume | q.s. to volume | q.s. to volume |

## Multiple-Dose Pharmacokinetic Profile

- Serum concentrations of HPC in patients who after a loading dose of 1000 mg daily for 5 days were treated with either 1000 mg HPC every week or with 1000 mg every 2 weeks
- From Onsrud, 1985

## Tocolytic Use – Study 002

|  | 17P
(N=310)
% | Placebo
(N=153)
% |
| --- | --- | --- |
| Tocolytic use | 	12.9 | 	11.8 |

**Tocolytic Use – Study 002**

## Stillbirth Rates

|  |  |  |  |
| --- | --- | --- | --- |
|  | 17P
(N=404)
n (%) | Placebo
(N=209)
n (%) | P value |
|  |  |  |  |
| Stillbirths | 7 (1.7) |    4 (1.9) | 0.8769 |
|    Antepartum
   Intrapartum
 | 6 
1       | 2
2 |  |
|  |  |  |  |

**Stillbirths – Study 001/002**

## Cardiac Findings – Summary

- Low rate of cardiac anomalies observed at birth in both 17P and placebo groups (0.5% vs 0.5%)
- Patent ductus arteriosus observed in 2.4% of 17P cases and 5.4% of placebo cases
- At Follow-Up Study examination
- Infants in the 17P
- Murmurs – 4.6%
- Irregular rhythm – 0.5%
- No functional disabilities noted by history or physical exam

## Corticosteroid Use At Baseline – Study 002

**	**

|  | 17P
(N=310)
n (%) | Placebo
(N=153)
n (%) | P value |
| --- | --- | --- | --- |
| 
Any corticosteroid use
    (before randomization)

    Inhaled corticosteroid use         | 	5 (1.6%)
1 (0.3) | 	8 (5.2%)
7 (4.6) | 0.0324 |

## Corticosteroids Use

- Time points for data collection
- At baseline
- Weekly during prenatal visits
- Preterm labor admissions
- Corticosteroid use collected _only_ prior to the birth hospitalization
- No specific guidelines were given to site investigators regarding use

## Kester – Effects of Prenatal 17-HPC on Adolescent Males (1984)

- Examined 25 adolescent males exposed to 17-HPC prenatally
- Assessed impact on recreational interests and psychosexual development in boyhood
- No difference in psychological testing noted between  adolescents exposed to 17-HPC and unexposed controls
- No impact on results based on total dosage of 17-HPC, duration of exposure, or period of gestation
- Kester PA. *Arch Sex Behav*. 1984;13(5):441-55

## Table 4‐10.	Neonatal Morbidity and Mortality for Live Births (1 of 2)

| Morbidity | 17PN=295n (%) | PlaceboN=151n (%) | P value |
| --- | --- | --- | --- |
| Transient tachypnea | 11 (3.7) | 11 (7.3) | 0.0990 |
| Respiratory distress syndrome (RDS) | 29 (9.9) | 23 (15.3) | 0.0900 |
| Bronchopulmonary dysplasia (BPD) | 4 (1.4) | 5 (3.3) | 0.1730 |
| Persistent pulmonary hypertension | 2 (0.7) | 1 (0.7) | 1.0000 |
| Ventilator support | 26 (8.9) | 22 (14.8) | 0.0616 |
| Supplemental oxygen | 45 (15.4) | 36 (24.2) | 0.0248 |
| Patent ductus arteriosus  | 7 (2.4) | 8 (5.4) | 0.1004 |
| Seizures | 3 (1.0) | 0 | 0.5541 |
| Any intraventricular hemorrhage (IVH) | 4 (1.4) | 8 (5.3) | 0.0258 |
| Grade 3 or 4 IVH | 2 (0.7) | 0 | 0.5511 |
| Other intracranial hemorrhage | 1 (0.3) | 2 (1.3) | 0.2628 |

## Plasma Concentrations of 17-HPC over Time

- Individual serum concentrations of HPC in 5 patients after intramuscular administration of a single dose of 1000 mg (arrow)
- From Onsrud, 1985

## Single Dose Pharmacokinetics of 17-HPC (1000 mg)

| Parameter | Mean ± SD | n |
| --- | --- | --- |
| Cmax (ng/mL) | 27.8 ± 5.3 | 5 |
| Tmax (days) | 4.6 ± 1.7 | 5 |
| t1/2 (days) | 7.8 ± 3.0 | 4 |
| AUC0-7 (ng•day/mL) | 118 ± 36 | 5 |
| AUC0-∞ (ng•day/mL) | 355 ± 136 | 4 |
| From Onsrud, 1985 |  |  |

## 17-HPC Teratogenicity Data in Mice

- No teratogenicity or maternal toxicity observed
- C57Bl/6J Mice exposed to 0.5, 5, and 50 mg/kg/d (0.1-10 X clinical dose) via subdermal pellets on gestation d 7-19 (n=8)1
- No teratogenicity observed
- ARS Swiss Webster Mice exposed to 42, 416, and 833 mg/kg (~10-200 X clinical dose) on d 6-15; n=11-152; SC

- 1Carbone 1993
- 2Seegmiller, 1983

## 17-HPC Teratogenicity Data in Rhesus and Cynomolgus Monkeys

- No drug related anomalies found in fetuses from either species of monkey
- Treatment initiated much earlier in gestation (first third) than what is indicated in humans (16-20 weeks)1
- No teratogenicity in Rhesus monkeys2

- 1Hendrickx *et al.* 1987
- 2Courtney and Valerio, 1968

## 17-HPC Mechanism of Action 

- In vitro receptor binding studies show 17-HPC:
- Better than either progesterone or 17-α-hydroxyprogesterone at inducing progesterone-responsive gene transcription1
- Comparable to progesterone in binding affinity for progesterone receptor2
- Displays greater selectivity for receptor isoform B (transcriptional activator) compared to isoform A (transcriptional repressor)
- 1Zeleznik et al. (abstract), 2006
- 2Attardi et al. (abstract), 2006

## Proposed Genomic and Nongenomic Mechanisms of Progesterone

- Modulates progesterone receptor activity
- Reduces estrogen receptor activity
- Blocks oxytocin induced uterine contractility
- Enhances tocolytic response
- Promotes local antiinflammatory effects
- Inhibits myometrial gap junctions

## Study 002 and HUAM Study: Sample Size Considerations

|  | Study 002 |  | HUAM Study |
| --- | --- | --- | --- |
| 1 previous PTD | 314 (67.8%) |  | 194 (76.4%) |
| >1 previous PTD | 149 (32.2%) |  | 57 (22.4%) |
| GA of worst previous PTB, mean (SD) | 29.7 (4.9) |  | 30.2 (4.9) |
| GA qualifying delivery (wk), mean (SD) | 30.8 (4.5) |  | ND |
| Year completed | 2002 |  | 1996 |
| MFMU Sites | 19 |  | 11 |
| Design | Interventional |  | Observational |

## 17-HPC Mechanism of Action 

- Not known
- Multiple pathways possible
- May be distinct from progesterone, though pharmacologically similar
- Progesterone inhibits myometrial contractility through
- Non-genomic mechanisms
- Genomic mechanisms

## Study 002: Preterm Birth <370 by Site

| Center | 17P
n/N   (%) | Placebo
n/N   (%) |
| --- | --- | --- |
| 	2 – Pittsburgh  | 	5/24	(20.8) | 	11/12	(91.7) |
| 	4 – Tennessee | 	13/30 	(43.3) | 	9/15 	(60.0) |
| 	8 – Alabama | 	23/86 	(26.7) | 	18/40 	(45.0) |
| 	9 – Detroit | 	5/16 	(31.3) | 	5/8 	(62.5) |
| 	11 – Cincinnati | 	3/9 	(33.3) | 	2/4 	(50.0) |
| 	13 – Wake Forest | 	7/13 	(53.9) | 	7/9 	(77.8) |
| 	15 – Ohio State | 	11/20 	(55.0) | 	4/8 	(50.0) |
| 	18 – Dallas | 	12/28 	(42.9) | 	8/11	(72.7) |
| 	20 – Utah | 	11/29 	(37.9) | 	7/14 	(50.0) |
| 	21 – Philadelphia | 	10/17 	(58.8) | 	3/7 	(42.9) |
| 	22 – Providence | 	1/3 	(33.3) | 	1/2 	(50.0) |
| 	23 – New York | 	2/6 	(33.3) | 	1/5 	(20.0) |
| 	25 – Cleveland | 	2/4 	(50.0) | 	1/2 	(50.0) |
| 	26 – Houston and 19 – San Antonio | 	3/10 	(30.0) | 	4/7 	(57.1) |
| 	27 – Chapel Hill and 17 – Miami | 	3/9 	(33.3) | 	1/6 	(16.7) |
| 	28 – Chicago and 14 – Chicago | 	4/6 	(66.7) | 	2/3 	(66.7) |

**Study 002: Preterm Birth <37****0**** by Site**

## Study 002: Secondary Pregnancy Outcomes

| Pregnancy Outcome | 17P 
N=310 
n (%) | Placebo N=153 
n (%) | P value |
| --- | --- | --- | --- |
| Delivery <350  | 67 (21.6) | 47 (30.7) | 0.0324 |
| Delivery <320  | 39 (12.6) | 30 (19.6) | 0.0458  |
| Spontaneous delivery <370 | 94 (30.3) | 69 (45.1) | 0.0017  |
| SPTD <370 due to pPROM | 26 ( 8.4) | 16 (10.5) | 0.4656 |
| SPTD <370 due to PTL | 67 (21.6) | 53 (34.6) | 0.0026  |
| SPTD <370 due to PTL or pPROM | 89 (28.7) | 69 (45.1) | 0.0005 |
| Indicated delivery <370  | 25 (8.1) | 15 (9.8) | 0.5309  |

## Genital/Reproductive Abnormalities

- Micropenis (17P)
- Born at 381 weeks gestation
- Aged 4.5 years at Follow-Up Study exam
- Genital exam at birth – normal
- Micropenis (17P)
- Born at 335 weeks gestation
- Aged 3.5 years at Follow-Up Study exam
- Infant with Down syndrome
- Common associated finding

## Genital/Reproductive Abnormalities

- Early puberty (17P)
- Born at 396 weeks gestation
- Aged 3.6 years at Follow-Up Study exam
- Breast buds observed at Follow-Up Study exam
- Obese female child
- 66 lbs (100th percentile BMI)
- Sparse pubic hair (Placebo)
- Born at 251 weeks gestation
- Aged 3.5 years at Follow-Up Study exam
- “Four or five long pubic hairs” at Follow-Up Study exam
- No other abnormalities noted

## Reproductive & Genitourinary Anomalies

- Infant 020-023 (17P)
- Born at 381 weeks gestation
- Aged 5 years at Follow-Up Study exam
- Labia “fused together” at Follow-Up Study exam
- Genital exam at birth – normal
- Multiple infant exams between 1 week and 3 years with normal exams
- Urogenital sinus fuses at 12 weeks of gestation
- Represents benign labial adhesions rather than labioscrotal fusion

## Reproductive & Genitourinary Anomalies

- Infant 018-032
- Born at 381 weeks gestation
- Aged 4 years at Follow-Up Study exam
- Genital exam at birth – normal
- Infant was reexamined 4 months later
- Same examiner
- Reported to be normal
- “Clitoris <5mm in transverse diameter”

## Physical Examination – Genital Abnormalities

- Genital/reproductive abnormalities
- 17P group – 1.5%
- Placebo group – 1.2%
- Abnormalities identified were
- Breast buds
- 17P female, 100% BMI
- Sparse pubic hair
- Placebo female, no other abnormalities
- Micropenis
- 17P male, genital exam at birth, normal
- 17P male, Down syndrome