Contraception

Research Grid

Contraceptive Research 2006-present	Description	Status	Collaboration
NEW LONG-ACTING PROGESTIN Formulation and sterilization of levonorgestrel butanoate, which will provide progestational activity for three months after a single injection. It is expected that it may have advantages over DMPA for female contraception and may be better than norethisterone enanthate incombination with an androgen for male contraception. A pharmacokinetic study in animals was completed.	Progestins suppress pituitary hormones and thus prevent ovulation. In the absence of suppression of ovulation, other mechanisms include thickening of cervical mucus and altering the secretion of hormones sufficiently to prevent conception.	A pharmacokinetic study in men and women will be needed.	This is a joint project of NICHD, CONRAD and WHO.
NOVEL MALE LEADS One involves a peptide, occludin, conjugated to a mutant FSH that targets the testis and is designed to elicit the release of premature sperm. Inhibition of critical sperm function is the intent of other activities, in particular those focused on retinoic acid receptor, factors required for releasing motile sperm (Eppin), sperm membrane calcium channels (CatSper), and enzymes required for energy production (GAPDHS). Selective small molecule inhibitors have been identified for several of the validated targets	These new methods would either disrupt sperm production (in the testis), sperm maturation (in the epididymis), or sperm function (after ejaculation). Interference with sperm motility prevents fertilization.	High throughput screening will be required to optimize inhibitory small molecules. Alternative delivery system of the peptide complex will have to be evaluated.	None
NOVEL FEMALE LEADS Four target molecules have been identified as potential leads for novel female contraceptives. For three targets, inhibitory peptides have been developed and their half-life extended by PEGylation. One target is the GnRH II receptor, which predominates in reproductive tissue. Agonistic and antagonistic peptides have been made and show selectivity for the GnRH II receptor rather than the GnRH I receptor.	These molecules are important to establish pregnancy.	Isolation and anti-fertility testing of inhibitory peptides by vaginal application in mice, and then other species.	NICHD synthesis facility is making the GnRH II receptor antagonists.
VAGINAL CONTRACEPTION A Phase II contraceptive effectiveness study with 6% cellulose sulfate (CS) vaginal gel has been completed in the U.S. The results were very satisfactory – as good as or better than nonoxynol-9, but with less vaginal irritation.	A less irritating replacement for nonoxynol-9 as a vaginal spermicide is needed.	A Phase III study would be required by the FDA for registration.	An industrial partner is required to underwrite the costs of the Phase III trial.
DUAL PROTECTION Phase III contraceptive trial about to start with a new single-size diaphragm (SILCS) to be used with a gel that may have dual protective capabilities.	Phase III trial is a six-month contraceptive study in 450 couples randomized to use the device with either BufferGel or Nonoxynol-9.	This is the only trial needed for registration and a 510(k) submission for the device. If over-the counter status is to be sought, additional studies will be required.	An industrial partner would be required for manufacturing and marketing the device.
EMERGENCY CONTRACEPTION Pilot studies with meloxicam, a Cox-2 inhibitor available in many countries, have shown that it has the potential to be used either as a stand-alone non-steroidal product or combined with levonorgestrel for emergency contraception. Inhibition of Cox-2 results in inhibition of follicular rupture, but luteal development is normal, thus ensuring normal menstrual cycles.	Emergency contraceptives can be taken after unprotected intercourse to prevent ovulation. There is a need for a non-hormonal alternative to the levonorgestrel pill presently available to reduce side effects.	A dose-finding study funded by the Hewlett Foundation is complete. A Phase II efficacy study is now needed.	Partners for the Phase II study have yet to be identified.
MALE HORMONAL CONTRACEPTION A Phase IIb study of norethisterone enanthate and testosterone undecanoate given intramuscularly every 8 weeks is being tested as a male hormonal contraceptive. This is a multi-site study in 7 countries. The first volunteers have been enrolled.	There are no male contraceptive options other than vasectomy (mostly irreversible) or condoms (not practical for long-term use). This will provide a male hormonal method.	The study will take approximately 3 years to complete. If the results are favorable, a Phase III trial will be required.	This is a joint project of CONRAD and WHO. Bayer Schering Pharma has donated the drugs for the study.

Contraceptive Research 2006-present

Description

Status

Collaboration

NEW LONG-ACTING PROGESTIN Formulation and sterilization of levonorgestrel butanoate, which will provide progestational activity for three months after a single injection. It is expected that it may have advantages over DMPA for female contraception and may be better than norethisterone enanthate incombination with an androgen for male contraception. A pharmacokinetic study in animals was completed.

Progestins suppress pituitary hormones and thus prevent ovulation. In the absence of suppression of ovulation, other mechanisms include thickening of cervical mucus and altering the secretion of hormones sufficiently to prevent conception.

A pharmacokinetic study in men and women will be needed.

This is a joint project of NICHD, CONRAD and WHO.

NOVEL MALE LEADS One involves a peptide, occludin, conjugated to a mutant FSH that targets the testis and is designed to elicit the release of premature sperm. Inhibition of critical sperm function is the intent of other activities, in particular those focused on retinoic acid receptor, factors required for releasing motile sperm (Eppin), sperm membrane calcium channels (CatSper), and enzymes required for energy production (GAPDHS). Selective small molecule inhibitors have been identified for several of the validated targets

These new methods would either disrupt sperm production (in the testis), sperm maturation (in the epididymis), or sperm function (after ejaculation). Interference with sperm motility prevents fertilization.

High throughput screening will be required to optimize inhibitory small molecules. Alternative delivery system of the peptide complex will have to be evaluated.

None

NOVEL FEMALE LEADS Four target molecules have been identified as potential leads for novel female contraceptives. For three targets, inhibitory peptides have been developed and their half-life extended by PEGylation. One target is the GnRH II receptor, which predominates in reproductive tissue. Agonistic and antagonistic peptides have been made and show selectivity for the GnRH II receptor rather than the GnRH I receptor.

These molecules are important to establish pregnancy.

Isolation and anti-fertility testing of inhibitory peptides by vaginal application in mice, and then other species.

NICHD synthesis facility is making the GnRH II receptor antagonists.

VAGINAL CONTRACEPTION A Phase II contraceptive effectiveness study with 6% cellulose sulfate (CS) vaginal gel has been completed in the U.S. The results were very satisfactory – as good as or better than nonoxynol-9, but with less vaginal irritation.

A less irritating replacement for nonoxynol-9 as a vaginal spermicide is needed.

A Phase III study would be required by the FDA for registration.

An industrial partner is required to underwrite the costs of the Phase III trial.

DUAL PROTECTION Phase III contraceptive trial about to start with a new single-size diaphragm (SILCS) to be used with a gel that may have dual protective capabilities.

Phase III trial is a six-month contraceptive study in 450 couples randomized to use the device with either BufferGel or Nonoxynol-9.

This is the only trial needed for registration and a 510(k) submission for the device. If over-the counter status is to be sought, additional studies will be required.

An industrial partner would be required for manufacturing and marketing the device.

EMERGENCY CONTRACEPTION Pilot studies with meloxicam, a Cox-2 inhibitor available in many countries, have shown that it has the potential to be used either as a stand-alone non-steroidal product or combined with levonorgestrel for emergency contraception. Inhibition of Cox-2 results in inhibition of follicular rupture, but luteal development is normal, thus ensuring normal menstrual cycles.

Emergency contraceptives can be taken after unprotected intercourse to prevent ovulation. There is a need for a non-hormonal alternative to the levonorgestrel pill presently available to reduce side effects.

A dose-finding study funded by the Hewlett Foundation is complete. A Phase II efficacy study is now needed.

Partners for the Phase II study have yet to be identified.

MALE HORMONAL CONTRACEPTION A Phase IIb study of norethisterone enanthate and testosterone undecanoate given intramuscularly every 8 weeks is being tested as a male hormonal contraceptive. This is a multi-site study in 7 countries. The first volunteers have been enrolled.

There are no male contraceptive options other than vasectomy (mostly irreversible) or condoms (not practical for long-term use). This will provide a male hormonal method.

The study will take approximately 3 years to complete. If the results are favorable, a Phase III trial will be required.

This is a joint project of CONRAD and WHO. Bayer Schering Pharma has donated the drugs for the study.