Jason Woo, MD, MPH, FACOG Contraceptive and Reproductive Health Branch CPR/NICHD/NIH

Jason Woo, MD, MPH, FACOG

Contraceptive and Reproductive Health Branch

CPR/NICHD/NIH

None

Identify challenges to successful use of existing contraceptive methods to prevent unplanned pregnancies.

Describe novel areas for development of alternative forms and types of contraceptive methods.

Describe the leadership role of the National Institute of Child Health and Human Development in developing and advancing new contraceptive methods to address the problem of unplanned pregnancy around the world.

"Must it not then be acknowledged by an attentive examiner of the histories of mankind, that in every age and in every State in which man has existed, or does now exist That the increase of population is necessarily limited by the means of subsistence,That population does invariably increase when the means of subsistence increase, and,That the superior power of population is repressed, and the actual population kept equal to the means of subsistence, by misery and vice."

1.3 billion women age 15 -451.2 billion pregnancies from 1995-2000300 million were unintended700,000 women died as a result of an

unplanned pregnancyMore than 120 million women report being

sexually active, do not want to become pregnant, and are NOT using any form of contraception

* World Health Organization: www.who.int/whr/2005/chapter3/en/index3.html

62 million women age 15-4462% using contraception (38.2 million)89% “at risk” women using contraception14% NOT using any contraception

6.2 million pregnancies per yearUnintended: half (3.1 million)

44% result in births42% result in abortion

4 million births per year1 million miscarriages and stillbirths1.2 million abortions performed

Use of Contraception in the United States: 1982-2008, CDC

Improved child health and developmentMore effective inter-genertional transfer of

resourcesIncreased longevity and empowerment of

womenAttendant economic benefits to family and

communityReduces lifetime risk of chronic disease or

death from a pregnancy-related condition

Greater risk for depression and physical abuseHealth risks of pregnancy, including maternal deathChild born from an unplanned pregnancy is at

greater risk of:Low birth weightDying in its first year of lifeBeing abusedNot receiving sufficient resources for healthy

developmentIncreased risk of economic hardship, failure to

achieve educational and career goals, greater risk of parental relationship dissolution

Contraceptive Method Typical Use, Failure Rate

(%)

95% Confidence Interval

Rank

Female Sterilization Less than 1 NA Highest

Male Sterilization Less than 1 NA

All methods other than Sterilization

12.4 11.2 – 13.7

Injectable 6.7 4.3 – 10.5

Pill 8.7 7.2 – 10.5

Male Condom 17.4 14.8 – 20.5

Withdrawal 18.4 13.7 – 24.2

Periodic Abstinence 25.3 16.1 – 37.5

Spermicides 29.0 NA Least

Use of Contraception in the United States: 1982-2008, CDC

Survey of 14,000 French households (2003)33% of pregnancies over a 5 yr period were

unplanned65% of the unplanned pregnancies occurred

among women using contraceptionSurvey in the U.S. found 50% of unintended

pregnancies occurred among couples using some form of contraception (1998)

Overall rates of 60 to 70 percent in developing and developed countries

Over 580 million women worldwide use modern contraceptive methods

But 120 million people do not use any form of contraception

In US, the 7% of women at risk for unintended pregnancy and who use no method of contraception account for about half of all unintended pregnancies (1998)

Most current methods have an approx. 50% discontinuation use after one year, usually because of side effects

New Frontiers in Contraceptive Research: A Blueprint for Action

Released: January 20, 200413 Primary Recommendations

Identify and Validate Novel Contraceptive Targets

Generate a complete reproductive transcriptome and proteome, and define genetic and protein networks

Generate reproductive lipidomes and glycomes

Validate existing and emerging contraceptive targets

Enhance Contraceptive Drug Discovery, Development, and Clinical TestingDevelop high-throughput screening facilitiesFacilitate translational researchFacilitate the development of appropriate drug delivery

systemsDevelop new approaches to measure contraceptive

efficacy Integrate behavioral research at an early stage of

developmentDiscover, enhance, and promote potential health

benefits of existing and new methods, and intensify efforts to develop new contraceptive methods that are prophylactic for HIV infection and other STIs

Facilitate and Coordinate Future Implementation of Contraceptive Research and DevelopmentExpand public-private partnerships for

contraceptive developmentIncrease the participation of developing

countries in contraceptive developmentIncrease training and career development

opportunities in contraceptionEstablish an ongoing Forum on Contraceptive

Research and Development and create an Alliance for Contraceptive Development

4 percent of all genes may be uniquely and exclusively expressed in male germ cells

More than 200 human genes or other related genes in other species have been shown genetically to play roles in reproduction in vivo

Genes Involved in the Regulation of Male Reproduction in the Mouse

Promising New TargetsKey Areas for discovery:

Male spermatogenesis pathwaySperm maturation (both sperm and epididymal

proteins)Sperm capacitation, motility and chemotaxis in the

female reproductive tractProteins and molecules in the female reproductive

system (vagina, cervix, uterus and oviduct) – focus on epithelium

Sperm-egg interactions (both sperm and egg proteins and molecules)

Maturation and ovulation of the egg

Identify and characterize all genes and proteins uniquely or preferentially expressed in the testis, ovary, and reproductive tissues; and define the genetic and protein networks in cells relevant to reproduction, including construction of a protein interaction map for the sperm and egg Develop and apply selective screening methods to identify

classes of molecules that have been traditionally targeted by pharmaceuticals, including membrane proteins, enzymes, receptors and ion channels and transporter proteins

Define the reproductive transcriptome Verify, annotate, and standardize all gene expression data Determine the complete proteomes of the sperm and the egg Initiate long-term support for efforts to identify and

construct regulatory networks in reproductive cells, since genes and proteins do not act autonomously

Generate lipidomes and glycomes of the reproductive tract tissues and mature gametesDetermine the unique carbohydrate structures on

proteins and lipids in reproductive cellsDetermine the contents and organizations of lipid

domains within the membranes of reproductive tract cells

Determine the roles of carbohydrates and lipids in reproductive tract cells to identify targets for small molecules that could act selectively to disrupt membrane structure and function

Validate existing and emerging contraceptive targets by using forward and reverse genetic approaches with model organismsMake use of existing genetic models through

more in-depth phenotypic analysis, including characterization by both genomic and proteomic methods

Fund a small consortium of investigators for the sole purpose of completing the genetic validation of all potential targets

Newly established genetic models should be rapidly distribute to the community of reproductive biology scientists for prompt and comprehensive phenotypic analysis

Validated targets are only useful if compounds can be identified to modulate those targets in humans

Selection of lead molecules for development remains a challenge

Need a high throughput drug discovery approach

Conduct and support research and training to develop new contraceptive methods for men and women.

Conduct and support research on the safety and efficacy of existing contraceptive methods.

Support research and training in selected areas of Reproductive Health with a special focus on pelvic floor disorders.

Most U.S. and European pharmaceutical firms have recently abandoned contraceptive R&D

USAID is emphasizing contraceptive distribution over contraceptive R&D

WHO has downsized contraceptive R&D program

Guttmacher InstitutePopulation Council

International Committee for Contraception Research

CONRADConsortium for Industrial Collaboration in

Contraceptive Research (CICCR-CONRAD)PATH (Program for Appropriate Technology in

Health)Society of Family PlanningHHS – NIH, CDCUS AID (Agency for International Development)World Health OrganizationFamily Health International

Society for the Study of ReproductionSociety for Gynecologic InvestigationAmerican Society for Reproductive MedicineWorld Congress of Gynecology and ObstetricsWorld Congress of Fertility and SterilityWorld Congress on Human ReproductionSociety for Advancement of Reproductive

Care

Bixby Center – UCSFFamily Planning Fellowship

CDC Division of Reproductive Health (DRH)

ResearchContractFor New

Development

Support ContractsBiological Testing Facility

Chemical Synthesis Facility

Peptide Synthesis Facility

Support ContractsBiological Testing Facility

Chemical Synthesis Facility

Peptide Synthesis FacilityContraceptiveClinical Trials

Network

ContraceptiveClinical Trials

Network

ContraceptiveCenters Grants (U54)

Male Contraceptive

Development Program (U01)

ContraceptiveCenters Grants (U54)

Male Contraceptive

Development Program (U01)

InvestigatorInitiated Grants

Small Business,

Academic Researchers

University of Washington William Bremner, MD, PhD Male Contraception Research Center

University of Kansas Joseph Tash, PhD Center for Male Contraceptive Research and Drug

Development

Population Council, New York Regine Sitruk-Ware, MD Cooperative Contraceptive Research Center

Oregon Health & Science University Richard Stouffer, PhD Contraception by Blockade of Periovulatory Events in

Primates

Amory, J; University of Washington,Seattle, WABDADs as a male contraceptive

Clapham, D; Children's Hospital,

Boston, MAMale contraception/CatSper 1-4 sperm-specific ion channels

Herr, J; University of Virginia, Charlottesville, VATestis-specific serine threonine kinases 1 and 2

Matzuk, M; Baylor College of Medicine, Houston, TXInhibition of spermatogenic-specific proteins

O'Brien, D; University of North Carolina, Chapel Hill, NCInhibition of sperm-specific isoform of GAPDS

O’Rand; University of North Carolina, Chapel Hill, NCInhibition of eppin-semenogelin binding to inhibit sperm motility

Tereda, N; University of Florida, Gainesville, FLInhibition of a testis-specific isoform of adenine nucleotide translocase

Wolgemuth, D; Columbia University, New York, NYRentinoid antagonists for inhibition of spermatogenesis

Biological Testing Facility (SRI International)Full range of preclinical testing of new

compounds in both non-primates and primates.

Chemical Synthesis Facility (Evestra)Synthesis of bulk quantities (1 kg) of steroids and

smaller quantities of variety of other compounds under GMP

Peptide Synthesis Facility (NeoMPS)Bulk GMP production and formulation of the

GnRH antagonist acyline as well as production of a variety of other peptides.

Medicinal Chemistry Facility (U of KS, U of Minn) Focus on male contraception, now folded into

U54

Progesterone Receptor Modulators CDB-2914 (licensed to HRA Pharma and marketed in Europe)

Approved by FDA, August 13, 2010 CDB-4124 (licensed to Repros Therapeutics)

Estrogen Estradiol dinitrate ester (CDB-1357) (Evestra is licensing)

GnRH antagonist Acyline (CDB-3883)

Progestin Levonorgestrel butanoate (CDB-1830) Jointly developed with WHO

Androgenic Steroids Dimethandrolone undecanoate (CDB-4521) 11β-methyl-19 nortestosterone 17β-dodecylcarbonate (CDB-4730)

Nonhormonal antispermatogenic agents Indenopyridine (CDB-4022) Lonidamine analog (CDB-4776)

University of Pennsylvania

Kurt Barnhart, MD, MSCE

University of Pittsburgh

Mitch Creinin, MD

New York University

Livia Wan, MD

Columbia University

Carolyn Westhoff, MD

Johns Hopkins University

Anne Burke, MD

Western Reserve University

James Liu, MD

University of Texas, Southwestern

Bruce Carr, MD

*male sites

University of Oregon

Jeffrey Jensen, MD

University of Colorado

William Schlaff, MD

Eastern Virginia Medical School

David Archer, MD

University of Cincinnati

Michael Thomas, MD

California Family Health Council

Anita Nelson, MD, Ron Frezieres, MPH

University of Washington*

William Bremner, MD, PhD

Harbor UCLA*

Ronald Swerdloff, MD, Christina Wang, MD

Health Decisions (CRO)

• Phase I trial of four spermicide/microbicides

• Phase II trial of CDB-2914 (PRM) versus LNG as an emergency contraceptive (Obstet Gynecol. 2006;108:1089)• Phase II study of 50 mg and 10 mg doses of CDB-2914

• Phase III contraceptive efficacy trial of BufferGel with a diaphragm vs OrthoGynol cream with a diaphragm (Obstet Gynecol. 2007;110:577)

• Phase III open label trial of BufferGel with diaphragm

• Phase III contraceptive efficacy trial of C31G spermicidal gel vs Conceptrol

• Phase I trial of Nestorone gel + testosterone gel as a potential male contraceptive regimen (measuring gonadotropin supression) (J Clin Endocrinol Metab. 2009;94:2313)

Female contraceptives• Nestorone/Ethinyl Estradiol vaginal ring – In data

analysisPATH women’s condom - In Phase III studyLevonorgestrel patch - In Phase I/II studyLevonorgestrel butanoate – Phase I to begin August

‘11Estradiol-Progestin containing vaginal ring – In

product development

Male contraceptivesNesterone gel + testosterone gel (spermatogenesis

inhibition) - currently recruiting subjectsDimethandrelone undecanoate (oral androgen) –

Preparing for IND submission11-beta methyl-19-nortestosterone - IND application

Variety of mechanisms; e.g. R01, R03, R21, R43, R44Example areas of research include:

Effects of hormonal contraceptives on bone densityMale sterilization – intra vas deviceFemale sterilization – thermal transcervical deviceEffect of continuous versus sequential OCs FSH antisense strategy for contraceptionIdentification of male contraceptive lead

compoundsSelective blockers of oocyte maturationProgestin effects on uterine hemostasis and

angiogenesis

CONRADFormulation/manufacture of dosage forms of

levonorgestrel butanoateIn vitro screening of candidate microbicides

Family Health InternationalCochrane Collaboration reviews – Fertility

regulationFocused ultrasound device for vasectomy

WHOSupport for database for the development of

multiple guidance documents for international family planning (i.e. Medical Eligibility Criteria for Contraceptive Use)

Infrastructure support for WHO Contraception and HIV activities

Use of new biotechnology (genomics, proteomics, bioinformatics) to identify and develop new male and female nonhormonal contraceptives

Female contraceptive development (hormonal)

(with a focus on safer methods for obese women)

Male contraceptive development (hormonal)

Epidemiologic studies of contraceptive safety

Spermicide/microbicide studies

Expansion of a current program to emphasize development of non-hormonal male and female contraception

Take advantage of advances in areas such as genomics, proteomics and bioinformaticsTarget identification Target characterization (structural analysis of

binding sites)Target validation (? blocking = contraception)Target specificity (w/ sensitive expression assays)Lead identification (High Throughput Screening)Lead optimization (molecular modeling)

• Search for safer female hormonal contraception (with a focus on safer methods for obese

women)

• Replace ethinyl estradiol with estradiol, nitroestrogens

• New methods of administration (nanopreparations for intranasal or injection)

• Epidemiologic studies of the safety of hormonal contraception in overweight/obese women

• Focus on development of non-hormonal methods