Transcript Contraception

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 -45
 1.2 billion pregnancies from 1995-2000
 300 million were unintended
 700,000 women died as a result of an unplanned
pregnancy
 More 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 15-44
 62% using contraception (38.2 million)
 89% “at risk” women using contraception
 14% NOT using any contraception
 6.2 million pregnancies per year
 Unintended: half (3.1 million)
 44% result in births
 42% result in abortion
 4 million births per year
 1 million miscarriages and stillbirths
 1.2 million abortions performed
Use of Contraception in the United States: 1982-2008, CDC
 Improved child health and development
 More effective inter-genertional transfer of resources
 Increased longevity and empowerment of women
 Attendant economic benefits to family and community
 Reduces lifetime risk of chronic disease or death from
a pregnancy-related condition
 Greater risk for depression and physical abuse
 Health risks of pregnancy, including maternal death
 Child born from an unplanned pregnancy is at greater risk
of:
 Low birth weight
 Dying in its first year of life
 Being abused
 Not receiving sufficient resources for healthy development
 Increased 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
Use of Contraception in the United States: 1982-2008,
CDC
Least
 Survey of 14,000 French households (2003)
 33% of pregnancies over a 5 yr period were unplanned
 65% of the unplanned pregnancies occurred among
women using contraception
 Survey 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
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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, 2004
 13 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 Testing
 Develop high-throughput screening facilities
 Facilitate translational research
 Facilitate the development of appropriate drug delivery
systems
 Develop new approaches to measure contraceptive efficacy
 Integrate behavioral research at an early stage of development
 Discover, 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 Development
 Expand public-private partnerships for contraceptive
development
 Increase the participation of developing countries in
contraceptive development
 Increase training and career development opportunities
in contraception
 Establish 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 Targets
 Key Areas for discovery:
 Male spermatogenesis pathway
 Sperm maturation (both sperm and epididymal proteins)
 Sperm capacitation, motility and chemotaxis in the female
reproductive tract
 Proteins 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
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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 gametes
 Determine the unique carbohydrate structures on
proteins and lipids in reproductive cells
 Determine 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 organisms
 Make 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 Institute
 Population Council
 International Committee for Contraception Research
 CONRAD
 Consortium for Industrial Collaboration in Contraceptive
Research (CICCR-CONRAD)
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PATH (Program for Appropriate Technology in Health)
Society of Family Planning
HHS – NIH, CDC
US AID (Agency for International Development)
World Health Organization
Family Health International
 Society for the Study of Reproduction
 Society for Gynecologic Investigation
 American Society for Reproductive Medicine
 World Congress of Gynecology and Obstetrics
 World Congress of Fertility and Sterility
 World Congress on Human Reproduction
 Society for Advancement of Reproductive Care
 Bixby Center – UCSF
 Family Planning Fellowship
 CDC Division of Reproductive Health (DRH)
Research
Contract
For New
Development
Contraceptive
Centers Grants (U54)
Male Contraceptive
Development Program (U01)
Small
Business,
Academic
Researchers
Support Contracts
Biological Testing Facility
Chemical Synthesis Facility
Peptide Synthesis Facility
Investigator
Initiated
Grants
Contraceptive
Clinical Trials
Network
 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
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Amory, J; University of Washington,
Seattle, WA
BDADs as a male contraceptive
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Clapham, D; Children's Hospital,
Boston, MA
Male contraception/CatSper 1-4 spermspecific ion channels
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Herr, J; University of Virginia,
Charlottesville, VA
Testis-specific serine threonine kinases 1
and 2
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Matzuk, M; Baylor College of Medicine,
Houston, TX
Inhibition of spermatogenic-specific
proteins
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O'Brien, D; University of North Carolina,
Chapel Hill, NC
Inhibition of sperm-specific isoform of
GAPDS
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O’Rand; University of North Carolina,
Chapel Hill, NC
Inhibition of eppin-semenogelin binding to
inhibit sperm motility
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Tereda, N; University of Florida,
Gainesville, FL
Inhibition of a testis-specific isoform of
adenine nucleotide translocase
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Wolgemuth, D; Columbia University,
New York, NY
Rentinoid 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 Oregon
Jeffrey Jensen, MD
University of Pittsburgh
Mitch Creinin, MD
University of Colorado
William Schlaff, MD
New York University
Livia Wan, MD
Eastern Virginia Medical School
David Archer, MD
Columbia University
Carolyn Westhoff, MD
University of Cincinnati
Michael Thomas, MD
Johns Hopkins University
Anne Burke, MD
Western Reserve University
James Liu, MD
University of Texas, Southwestern
Bruce Carr, 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)
*male sites
• 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
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Nestorone/Ethinyl Estradiol vaginal ring – In data analysis
PATH women’s condom - In Phase III study
Levonorgestrel patch - In Phase I/II study
Levonorgestrel butanoate – Phase I to begin August ‘11
Estradiol-Progestin containing vaginal ring – In product
development
Male contraceptives
 Nesterone gel + testosterone gel (spermatogenesis
inhibition) - currently recruiting subjects
 Dimethandrelone undecanoate (oral androgen) –
Preparing for IND submission
 11-beta methyl-19-nortestosterone - IND application
 Variety of mechanisms; e.g. R01, R03, R21, R43, R44
Example areas of research include:
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Effects of hormonal contraceptives on bone density
Male sterilization – intra vas device
Female sterilization – thermal transcervical device
Effect of continuous versus sequential OCs
FSH antisense strategy for contraception
Identification of male contraceptive lead compounds
Selective blockers of oocyte maturation
Progestin effects on uterine hemostasis and angiogenesis
 CONRAD
 Formulation/manufacture of dosage forms of
levonorgestrel butanoate
 In vitro screening of candidate microbicides
 Family Health International
 Cochrane Collaboration reviews – Fertility regulation
 Focused ultrasound device for vasectomy
 WHO
 Support 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
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Use of new biotechnology (genomics, proteomics,
bioinformatics) to identify and develop new male and
female nonhormonal contraceptives
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Female contraceptive development (hormonal)
(with a focus on safer methods for obese women)
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Male contraceptive development (hormonal)
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Epidemiologic studies of contraceptive safety
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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 bioinformatics
 Target 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