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APPENDIX A Examples of Progress and Impecliments in Contraceptive Research and Development This appendix provides an update on some of the targets identified as promising in the 1996 IOM report (Institute of Medicine, 1996) and describes what progress has been made and what impediments still exist. It is not meant to be comprehensive but rather is meant to highlight examples of some of the changes that have taken place since 1996. Specifi- cally, updates on microbicide development, male contraceptives, anti- progestins, and immunocontraception are provided. Table A.1 lists a variety of reversible female contraceptives that have been approved since 1996 or that are currently under development. All of the contraceptives listed are essentially variations of previous methods that have been avail- able for as long 20 to 40 years. Thus far, no truly novel targets that could provide completely new approaches to contraception have advanced to the clinical testing stage. ADVANCES IN MICROBICIDES AND SPERMICIDES The worldwide HIV/AIDS epidemic has spurred a great deal of activity in the area of vaginal microbicide development. Microbicides entail a wide variety of formulations that include chemicals, antibodies, or buffers that can prevent the transmission of sexually transmitted infec- tions (STIs) and in many cases that also act as spermicidal contraceptives. Several microbicides are already in clinical trials to test their efficacy in preventing pregnancy and STI transmission, but many others are also at earlier stages of development. Examples of microbicides in development are listed in Table A.2. 163

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64 NEW FRONTIERS IN CONTRACEPTIVE RESEARCH TABLE A.1 Female Contraceptives: Changes Since 1996 Contraceptive Type and Use Effectiveness Mechanism of Action Rate and Description Develops Reversible, FDA approved Mirena Levonorgestrel- ~ 99% in the LNG renders the endometrium Approves releasing first year. unresponsive to estrogen, up to5 y' intrauterine Similar in which is responsible for growth of use in: system form to a of uterine lining in preparation Develope (LNG IUS). T-shaped for pregnancy. LNG also manufact IUD. renders the cervical mucus Distribute Vertical hostile to sperm penetration, Laboratory portion hence preventing fertilization. developir of T bears a small cylinder containing LNG. NuvaRing Hormone/ 98%-99% The first monthly hormone- Developed monthly when used releasing vaginal ring used for FDA on ( vaginal ring. as directed. birth control. A soft, flexible transparent ring A/ inch thick with an outer diameter of 2 inches containing etonorgestrel and ethinyl estradiol. Impedes ovulation and implantation. Unlike Cervical caps and diaphragms, the exact placement in the vagina is not critical for it to be effective. The ring is left in the vagina for 3 weeks, after which it is removed for 1 week and then a new ring is inserted. Progesterone Hormone/ Over 98.5% Inhibits cervical mucus Approver vaginal ring vaginal ring. when used production and prevents as directed. ovulation in lactating women. Lunelle Hormone/ 99% Combines medoxyprogesterone Approves monthly acetate and estradiol cypionate, Manufact injection. which suppress ovulation, the comp thicken the cervical mucus, October 2 and thin the endometrium. because c Intramuscular injections are potency a given by a health care provider failure. every 28 to 30 days.

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APPENDIX A 165 Development and FDA Approval Side Effects Atrium on, ~ growth Oration cus ration, cation. one- sed for xible Inch thick of 2 inches '1 and les lion. d Placement .cal for it is left in after 1 week nserted. romen. esterone pionate, In, us, am. ~ are Provider Approved by FDA in December 2000 for up to 5 years of use. Approved for 5 years of use in most countries where it is available. Developed by Population Council and manufactured by Schering Oy Laboratories. Distributed in the United States by Berlex Laboratories. Widely used in Europe and developing countries. Developed by Organon, Inc. Approved by FDA on October 3, 2001. Approved only in Chile. Approved by FDA in October 2001. Manufactured by Pharmacia Corporation; the company initiated a voluntary recall October 2002 of Lunelle prebilled syringes because of a lack of assurance of full potency and possible risk of contraceptive failure. Irregular bleeding and amenorrhea, rare hormone-related side effects. Health benefits include reduced number of days of bleeding and increase in hemoglobin levels. Irregular bleeding, weight gain, breast tenderness, nausea, changes in mood. Minimal. Same as those for combination oral hormonal contraceptives. continued

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166 TABLE A.1 Continued NEW FRONTIERS IN CONTRACEPTIVE RESEARCH Effectiveness Mechanism of Action Contraceptive Type and Use Rate and Description Develops Implanon Hormone/ 99% Implanon is a progestogen-only FDA app: implant. contraceptive implant; a small, Organon flexible rod, 40 millimeters (mm) long and 2 mm in diameter inserted under the skin on the inside of the upper arm. Contains 68 mg of etonorgestrel released over the 3-year life of the device. Inhibits ovulation and thickens the cervical mucus. Norplant Hormone/ 97-99% Six thin, flexible silicone capsules, Received implant. 33 mm long and 2.4 mm in no longer diameter, containing 36 mg of because ~ LNG, for a total of 216 ma. U.S. mark The capsules are inserted under in 58 cow the skin in a minor surgical Council. procedure; this method is effective for up to 5 years. Jadelle Hormone/ 99% implant. Two flexible silicone rods filled with LNG inserted under the skin (very similar to Norplant). Each Jadelle rod is 43 mm long and 2.5 mm in diameter and contains 5 mg of LNG (total of 150 mg); effective for up to 5 years. Received approved However United St Populatic by Scheri Ortho Evra Transdermal 99.6% when A transdermal patch is applied Received hormonal used as each week for 3 weeks and is November system. directed. then removed for 1 week. Produced It uses ethinyl estradiol and norelgestromin. Depo-Provera Hormone 97-99% when An intramuscular injection of Received injection. used as depo-medroxyprogesterone produced directed. acetate given every 12 weeks. Seasonale Hormonal oral Over99% Used for 84 days before a 7-day Develope contraceptive when used placebo instead of the usual Received as directed. 21-day/7-day cycle. It contains LNG and ethinyl estradiol.

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APPENDIX A 167 Development and FDA Approval Side Effects ,en-only small, hers (mm) eter on the rgestrel ~ life of ration ~1 mucus. ~ capsules, I in mg of fig. id under ,ical iS rs. ds filled er the skin ate. Each fig and ~ contains 50 mg); rs. applied and is ok. and ion of tone reeks. a 7-day Usual ontains dol. FDA approved and marketed by Organon International since 1998. Received FDA approval in 1990 but is no longer available in the United States because Wyeth Ayerst took it off the U.S. market. Norplant has been approved in 58 countries. Developed by Population Council. Received FDA approval in 1996; presently approved for use for up to 5 years. However, it is not yet available in the United States. Developed by the Population Council and manufactured by Schering Oy Received FDA approval on November 20, 2001. Produced by Ortho-McNeil. Received FDA approval in 1992, produced by Pfizer. Developed by Barr Laboratories, Inc. Received FDA approved in September 2003. Irregular bleeding, weight gain, acne, headache, and breast tenderness. Irregular bleeding, headache, weight gain, nausea, and acne. Irregular bleeding, weight gain, headaches, acne, and mood changes. Same as those for combination oral hormonal contraceptives. Amenorrhea. Same as those for combination oral hormonal contraceptives. continued

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168 TABLE A.1 Continued NEW FRONTIERS IN CONTRACEPTIVE RESEARCH Contraceptive Type and Use Effectiveness Mechanism of Action Rate and Description Develops Cyclessa Hormonal oral contraceptive Over 99% Desogestrel/ethinyl estradiol. when used as directed. ~ 93% over 1 year of typical use. Received Decembe Develope Yasmin Hormonal oral Over99% Yasmin is amonophasic birth Received contraceptive when used controlpill. Each of the first Develope as directed. 21 pills contains the same amount Yasmin 2 ~93% over of estrogen (ethinyl estradiol) on May 2 1 year of and progestin (drospirenone). Develope typical use. LNG Hormonal oral Reduces the Believed to act as an EC FDA app (Levonorgestrel) contraceptive risk of principally by preventing following Known as Plan B pregnancy ovulation or fertilization; it may the only ~ when used for from ~ 8% also inhibit implantation, but is Develope emergency to 1.1% not effective once implantation (WCC) fit contraception following a has begun. Itis administered other not (EC). single act of within 72 hours of unprotected submitter unprotected intercourse for EC as two use to FD sex. consecutive doses (12 hours research' apart) of 0.75 mg of LNG, a research ~ totally synthetic progestogen Health In (total dose of 1.5 mg). of Califor Children' Pittsburg: (WHO). E of intent i from the LNG and Emergency oral Combined LNG and ethinylestradiol. Received ethinyl contraceptive EC is 75% Develope estradiol tablets effective. Preven Emergency oral 74% effective LNG and ethinyl estradiol. FDA app: Emergency contraceptive (wish no The PREVEN Emergency Develope Contraceptive contraception, Contraceptive regimen uses Kit 7.2% the Yuzpe method. Therapy pregnancies must be initiated as soon as expected; possible within 72 hours after with Yuzpe unprotected intercourse. method, 1.9% pregnancies expected.)

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APPENDIX A 169 Development and FDA Approval Side Effects radial. c birth first be amount adiol) none). g a; it may n, but is unction ,tered Protected 10 ours G. a togen dol. uses rapy In as s after Received FDA approval on December 20, 2000. Developed by Organon, Inc. Received FDA approval in May 2003. Developed by Berlex Laboratories. Yasmin 28 was approved by the FDA on May 2001, and earlier in Europe. Developed by Schering AG. FDA approved Plan B in July 1999 for EC following unprotected sex and is currently the only progestin-only EC approved by FDA. Developed by Women's Capital Corporation (WCC) financed largely by foundations and other not-for-profit organizations. WCC submitted an application for nonprescription use to FDA on April 21, 2003; supporting research was conducted by not-for-profit research organizations, including Family Health International (FHI), the University of California at San Francisco, the Children's Hospitals of Los Angeles and Pittsburgh, and the World Health Organization (WHO). Barr Laboratories, Inc., signed a letter of intent in October 2003 to acquire Plan B from the WCC. Received FDA approval on April 29, 2003. Developed by Barr Laboratories, Inc. FDA approved as of June, 1999. Developed by Gynetics, Inc. Same as those for combination oral hormonal contraceptives. Same as those for combination oral hormonal contraceptives, except for less bloating than that with other hormonal methods. Produces much less vomiting and nausea than other ECs containing both progestin and estrogen. Vomiting and nausea are potential side effects of EC pills. Vomiting and nausea are potential side effects of EC pills. continued

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170 TABLE A.1 Continued NEW FRONTIERS IN CONTRACEPTIVE RESEARCH Effectiveness Mechanism of Action Contraceptive Type and Use Rate and Description Develops Leah's Shield Vaginal barrier ~ 85% over One size, reusable vaginal barrier Develope used with a 1 year of use. method made of silicone with a March 14 spermicidal cup-shaped design and a valve, collabora lubricant. and loop for easy removal. and PHI. FemCap Vaginalbarrier. 77.2% over Silicone rubber cervical cap in FemCap, 1 year of use. three sizes with a brim designed March 28 to fit into the vaginal fornices. (EC Certi Available SILCS Vaginal barrier. Not tested A reusable vaginal barrier in Develope diaphragm yet. three sizes with a dome that Technolo, covers the cervix, a rim that fits with SIL( the vaginal fornices, and a brim being stun that conforms to the vagina. safety. Reality female Vaginal barrier. ~ 95% when Barrier. Made of plastic Collabora condom used as polyurethane (stronger then Medtech directed. latex). Today Sponge Vaginal barrier 89% to 91% The active ingredient in the FDA app when used Today Sponge is nonoxynol-9. Whitehal: according to another c instructions; currently otherwise use effectiveness rate is 84% to 87%.

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APPENDIX A 17 Development and FDA Approval Side Effects Al barrier Developed at Yama Inc. Approved by FDA Minimal. e with a March 14, 2002. Studies have been conducted a valve, collaboratively between CONRAD, Yama, vat. and FHI. cap in FemCap, Inc., received FDA approval on Minimal. designed March 28, 2003. Approved in Europe rnices. (EC Certificate No. 99-010901~. Available in Germany and Italy. ier in Developed at Program for Appropriate Minimal. that Technology in Health (PATH) in conjunction that fits with SILCS, Inc. The SILCS device is currently ~ a brim being studied for function, acceptability, and Gina. safety. than Collaboration between CONRAD and Minimal. Medtech Products Ltd. (in India). ~ the FDA application was withdrawn by Minimal. ynol-9. Whitehall-Robins Healthcare and then filed by another company; Allendale Pharmaceuticals; currently under review by FDA. continued

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172 TABLE A.1 Continued NEW FRONTIERS IN CONTRACEPTIVE RESEARCH Contraceptive Type and Use Effectiveness Mechanism of Action Rate and Description Develops Examples of Reversible Contraceptives in Development Progesterone receptor modulators Biodegradable implants, for example, Capronor Hormonal oral Unknown contraceptive but estrogen-free H orm one - releasing implants GnRH analogs Could be administered subdermally or other ways. Nestorone/EE . . . vaginal rmg Antigonadotropic. Prevents follicular growth and suppresses ovulation. NA NA Female hormonal Phase II trials contraceptive, indicate over progestin and 90% ovulation estrogen. suppression. Implants containing progestin are implanted under the skin of the arm or hip. The hormone is released gradually into the body for 12 to 18 months. Capronor II consists of two rods of polyte-caprolactone), each containing 18 mg of levonorgestrel (LNG). Capronor III is a single capsule of copolymer (caprolactone and trimethylenecarbonate) filled with 32 mg of LNG. With both systems, the implant remains intact during the first year of use and thus could be removed if needed. Over the second year, it biodegrades to carbon dioxide and water, which are absorbed by the body. A new group of drugs known as GnRH antagonists can be used to prevent the release of FSH and LH from the pituitary gland. The release of FSH and LH triggers ovulation and spermatogenesis (the development of sperm). Blocking the release of these hormones temporarily suppresses fertility for women and men. Suppresses follicular growth and ovulation. In FDA p None has One form GnRH an Developed Phase II t formulati in Swede

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APPENDIX A 173 Development and FDA Approval Side Effects ents Oppresses Breslin are in of the le is the body Donor II itch norgestrel single aprolactone rate) filled implant he first old be or the tdes to :er, which iy. known as be used to SH and land. The triggers Genesis army. these suppresses men. owth In FDA pipeline. None has been FDA approved. One form, Cetrorelix, is approved as a GnRH antagonist for other indications. Developed by the Population Council. Phase II trials completed, phase III trials formulation and manufacture by Q Pharma in Sweden. First-generation antagonists caused histamine release and local allergic reaction. New analogs are better tolerated. continued

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APPENDIX A 191 Stage of Development and FDA Approval Side Effects lion and lion and lion and d into the -scalpel and causes ng Oily skin, aggressiveness, increased muscle mass, decreased HDL levels. One of the earliest treatments for hypogonadism, researched as a male hormonal contraceptive since the 1970s. Efficacy study in China. Approved by FDA in August 2002. Now available in the United States. Expected launch in Europe by January 2004. Phase I and phase II trials completed in India. Currently in phase III clinical trials. Similar to those of other androgens. Similar to those of other androgens. Pain during procedure, although significantly reduced pain and complications compared with those after a traditional vasectomy. Because RISUG does not completely block the flow of sperm through the vas deferens, it appears not to have any of the negative side effects associated with vasectomies. Lack of toxicity remains to be confirmed. http: / /www.reproline.jhu.edu/english/6read/6issues/6network/vl8-3/ntl835a.html http: / /www.avert.org/condoms.htm#2 http: / /www.popcouncil.org/publications/popbriefs/pb8~2~_4.html http: / /www.malecontraceptives.org/methods/risug.htm

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92 NEW FRONTIERS IN CONTRACEPTIVE RESEARCH antagonists block the effect of GnRH coming from the hypothalamus to the pituitary gland and thereby decrease the production of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which reduces the levels of testosterone and sperm production. This approach has been shown in small pilot studies in the United States and Europe to be an effective method, although it has not been determined how long this sup- pression can be maintained, and larger follow-up studies are needed (Swerdloff et al., 1998~. To avoid undesirable side effects, GnRH antago- nists cannot be used in isolation. Testosterone is a necessary adjunct for the long-term use of such antagonists. This combination can be used to achieve azoospermia in a variety of ways, but one approach is to use a GnRH antagonist like acyline for a brief period such as 12 weeks at the initiation of a regimen to help with suppression of sperm production and then to stop the antagonist and use testosterone enanthate alone. Nonhormonal Methods Various orally active nonhormonal agents have been found in animal models to interfere with spermatogenesis without reducing testosterone levels. Lonidamine is a nonsteroidal, nonhormonal antispermatogenic agent that acts by premature exfoliation of germ cells from the seminiferous epithelium (De Martino et al., 1981; Silvestrini et al., 1984~. Although this was a novel mode of action, lonidamine was not developed as a male contraceptive because of its toxic effects on the liver and kidney, but it was used as an antitumor agent (Silvestrini, 1991; Silvestrini et al., 1984~. More recently, analogs of lonidamine were discovered that appeared to have the same action on the testes, but apparently without the toxicity of lonidamine (Cheng et al., 2001, 2002; Grima et al., 2001~. The Population Council, with the assistance of CICCR, the Mellon Foundation, and the National Institute of Child Health and Human Development (NICHD), has been working on the lead analog AF2364. Certain hexahyrdoindenopyridines have been reported to act as reversible male contraceptive agents (Cook et al., 1997~. A 28-day toxicity study with rats did not reveal any significant toxicity but did confirm the male contraceptive effect (Fail et al., 2000~. CICCR is discussing with the Research Triangle Institute the possibility of supporting some further studies with one of the lead compounds in this series, and it is hoped that collaboration with a pharmaceutical company will be possible. Lastly, a recent report has described the contraceptive activity of alky- lated imino sugars in male mice (van der Spoel et al., 2002~. When the lead compound, N-butyldeoxynojirimycin, was given orally, epididymal sperm had abnormal head shapes and lacked acrosomal antigens. The motility of the affected spermatozoa was abnormal, and the mice became

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APPENDIX A 193 infertile after 3 weeks of dosing. Fertility was regained in the fourth week after dosing ceased. This compound appeared to exert its effect through interference with the biosynthesis of glucosylceramide-based sphingo- lipids. These investigators are planning to develop this lead compound further. These are examples of exciting new contraceptive agents already at the proof-of-concept stage and merit further support as potential sec- ond-generation nonhormonal male contraceptives. UPDATE ON ANTIPROGESTINS AS FEMALE HORMONAL CONTRACEPTIVES The first antiprogestin was discovered in 1980. Since then, more than 400 compounds with antiprogestin activities have been synthesized (Hodgen, 1991), but only a handful have been tested with humans, includ- ing mifepristone (formerly Roussel-Uclaf, now Exelgene), onapristone and lilopristone (Schering AG), Org 31710 and Org 31806 (Organon, Inc.), and CDB 2914 (developed by NICHD). Antiprogestins can affect reproductive function because they bind to progesterone receptors in the hypothalamus, anterior pituitary, and uterus; and in doing so, they inhibit transcription of the genes that are normally activated by progesterone. In other words, the antiprogestins act as receptor antagonists. The contraceptive effects of antiprogestins depend on the dose and the time of the ovarian cycle at which they are administered. Various regimens of mifepristone have been tested, includ- ing a single postcoital dose for emergency contraception, as well as daily, weekly, and monthly regimens for conventional contraception (reviewed by Glasier, 2002~. The theoretical advantages of weekly or monthly re- gimes include exposure to lower total doses of the drug, but a disadvan- tage may be the difficulty in remembering to take the drug at the appro- priate time. In each case, inhibition of ovulation or significant disruption of endometrial development, or both, is thought to contribute to contra- ceptive efficacy. The contraceptive effects of mifepristone have been demonstrated most clearly in trials of emergency contraception. A single dose of 10, 50, or 600 milligrams (mg) of mifepristone each appears to be equally effec- tive in preventing pregnancy, even up to 120 hours after intercourse (Task Force on Postovulatory Methods of Fertility Regulation, 1999~. The mode of action of mifepristone when it is used as an emergency contraceptive depends on the stage of the menstrual cycle when it is taken. Given before ovulation, it prevents ovulation from occurring. Given after ovulation, the effect on the endometrium is indicative of impaired implantation. For the daily regimen, doses of mifepristone from 10 mg down to 0.1 mg have been tested. Doses between 2 and 10 mg daily have all been

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94 NEW FRONTIERS IN CONTRACEPTIVE RESEARCH shown to inhibit ovulation (Brown et al., 2002; Cameron et al., 1995; Croxatto et al., 1993; Ledger et al., 1992~. Sixty-five percent of women taking 2 mg/day and 88 percent of those taking 5 mg/day experienced amenorrhea. Although follicular activity continued during treatment, endometrial development was altered by doses ranging from 0.5 to 10 ma, suggesting that even if ovulation did occur, implantation would have been very unlikely. The contraceptive efficacy of daily low-dose mifepristone has been demonstrated in only two studies. In a study from Scotland and China (with 5 mg of mifepristone), 50 women used no other method of contraception and there were no pregnancies (Brown et al., 2002~. In a study of 32 women using 0.5 mg of mifepristone daily, 16 women com- pleted 6 months of use. In 141 cycles, there were five pregnancies (Marions et al., 1999~. In tests of mifepristone administered once per week, doses of 10 to 50 mg were associated with variable inhibition of ovulation (Chen and Xiao, 1997; Spitz et al., 1996), whereas doses of 5 and 2.5 mg did not inhibit ovulation (Gemzell-Danielsson et al., 1996~. However, all doses affected endometrial development. The efficacy of a weekly regimen has been tested in only one study involving 18 women (Marions et al., 1998~. In that study, three pregnancies occurred over 63 cycles. The administration of mifepristone once per month is thought to pre- vent pregnancy by inhibiting implantation. A number of studies have demonstrated that 200 mg of mifepristone given in the early luteal phase slows endometrial development without altering the timing of the next menses. Two studies have demonstrated greater than 95 percent contra- ceptive efficacy of 200 mg of mifepristone given within 2 days of the LH surge (Gemzell-Danielsson et al., 1993; Hapangama et al., 2001~. The lim- iting factor to this approach is the accurate detection of the LH surge, as the timing of mifepristone administration is critical. A few other antiprogestins have been tested in studies with humans as well, but much less extensively than mifepristone. Onapristone and lilopristone (Schering AG, Berlin) were both tested for their potential effects on reproductive function in humans, but onapristone was aban- doned after phase I studies demonstrated changes in liver function, and lilopristone has not been taken forward. Organon has published data on two antiprogestins, Org 31710 and Org 31806 (Kloosterboer et al., 1994), but clinical testing has not progressed past a very early stage. CDB 2914, which is structurally and functionally similar to mifepristone, has been shown to have no adverse effects in normally cycling women at doses of up to 200 mg (Passaro et al., 1997; Stratton et al., 2000~. A clinical trial of this compound as an emergency contraceptive has been completed and results are undergoing analysis. A new group of compounds called mesoprogestins has also been syn-

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APPENDIX A 195 thesized and characterized by lenapharm GmbH & Co. (lena, Germany). These compounds bind strongly to the progesterone receptor but have mixed agonistic and antagonistic activities in viva (Chwalisz et al., 2000~. Their antiproliferative effects on the endometrium are being investigated in studies with animal models, including primates, but no studies with humans have yet been published. Although antiprogestins have significant potential for contraceptive development, progress has been hindered by the political controversy surrounding mifepristone, which is licensed in many parts of the world as an abortifacient for use during early pregnancy. Lobbying efforts by groups opposed to abortion have led to limited interest and activity in the development of contraceptive antiprogestins by both the pharmaceutical industry and not-for-profit organizations, despite their potential for pre- venting unplanned pregnancy. UPDATE ON IMMUNOCONTRACEPTION The development of contraceptive vaccines has been pursued since the early days of contraceptive research, but progress in this field has been exceedingly slow, and the work has yet to produce a vaccine that is proven safe and effective for use in humans. Although various investigators had immunized animals with reproductive antigens since the early 1960s, the field of immunocontraception for humans was really launched as a result of a special consultation convened by WHO in Boston in 1973. This was followed by a symposium, Immunological Approaches to Fertility Control, the seventh in the series of Karolinska Symposia on Research Methods in Reproductive Endocrinology (1974~. Exploratory studies funded by WHO were undertaken to assess the feasibility of such an approach. WHO then held a symposium in Varna, Bulgaria, in 1975. Papers dealing with different potential antigens, including sperm, eggs, and hormones of the trophoblast, were presented and published (1975~. Consideration was also given to the safety of such approaches. Three main considerations that are critical to the success of such an immunological approach are the length of time that antibodies will be effective, the reversibility of the immuno- contraceptive, and the hypothetical potential for teratogenicity during periods when antibody levels are declining. At the time, there was great enthusiasm for a vaccine approach, which was novel and different from available contraceptive approaches, and WHO was supporting the work of about 30 scientists. Use of the ~ chain of human chorionic gonadotropin (phCG) was con- sidered to be the most promising lead at the time. Use of the whole phCG subunit to immunize female baboons showed that antibodies were pro- duced and pregnancy was prevented. A group in India pursued the use of

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96 NEW FRONTIERS IN CONTRACEPTIVE RESEARCH the whole ~ chain conjugated to tetanus toxoid. After appropriate safety tests, this preparation was administered to women, and it was found that when the circulating antibody was above a threshold value, women were protected from pregnancy; but some women did not respond, and charac- teristics that would predict a lack of response could not be identified be- forehand. This threw into question the practicality of a method in which antibody levels would have to be assessed at regular intervals. Another disadvantage of this approach was that antibodies were also raised against the ~ subunit of LH (pLH), and from a long-term perspective this was believed to be unsafe. WHO therefore concentrated on only small pieces of the phCG protein that were not present in pLH, but ensuring a good antibody response to these small peptides has proved difficult. In the intervening years, the WHO Task Force on Immunological Approaches to Fertility Control continued to support work in this field, but because of unsatisfactory results and declining funding, most leads were abandoned; the phCG approach was not, however. Delays occurred because of difficulties in selection of adjuvants5 and delivery vehicles that did not cause local reactions. Nonetheless, an application was submitted to the regulatory authorities in Sweden in May 2002 to carry out a phase I clinical trial with the current formulation of the phCG immunocontra- ceptive. A manufacturer of the immunocontraceptive that meets Good Manufacturing Practice standards has been identified, and preparation of clinical supplies of the formulation awaits funding. Lack of funding has also delayed the planned safety studies to be run concurrently with the phase I trial. The anti-hCG approach still appears to be the most practical because of several very attractive features. First, hCG has a clearly defined biologi- cal function that depends on its secretion into the maternal circulation, where it is readily accessible to antibodies. Circulating antibodies can act on the circulating hormone, and one does not have to be concerned with raising adequate antibody levels in an organ such as the fallopian tube or the uterus, which would be the case with many other potential antigens. High levels of pregnancy prevention have been observed in baboons and women if titers are high enough. The trial in India demonstrated that an antibody titer of 50 nanograms per milliliter (ng/ml) was effective in preventing pregnancy. The antibody response declined with time, and fertility was regained when titers fell below 35 ng/ml (Talwar et al., 1994~. Second, there is evidence from a study carried out in many developed countries that showed that women wanted a long-acting method that was 5A substance that is added to a vaccine to improve the immune response so that less vaccine is needed to produce more antibodies.

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APPENDIX A 197 not permanent but that could be taken without the knowledge of others, especially if it did not cause any endocrine or other metabolic distur- bances, had no overt signs of being used, and did not need storage or disposal. An hCG immunocontraceptive meets all of these criteria, which is not true of most other methods. Given the past results, it is likely that booster vaccinations would be needed every 2 to 3 months to maintain adequate antibody responses, but it is known from use of hormonal injectable contraception in women that even monthly injections can be acceptable in some settings (Snow et al., 1997~. The production of inex- pensive, home-use diagnostic kits would circumvent the problems of assessing antibody levels in cases where the actual titer was critical for contraception by allowing women to determine when the titer is too low to be effective. Such a kit could also screen out the nonresponders. Third, if reversibility became an issue in a small percentage of women, adminis- tration of exogenous progesterone to maintain the pregnancy is a potential solution. However, despite the promise and potential, the project is still at the early clinical trial stage some 30 years after work on this concept began. Some might question whether the work on phCG should be terminated, since the immunocontraceptive has not reached fruition in 30 years. On the other hand, 20 years of research and substantially greater funding have been devoted to the development of an anti-HIV vaccine, without success to date. The case for continued work on immunocontraceptives has recently been cogently put forth by Aitken (2002~. New funding sources, perhaps developed through grass-roots lobbying from consumers wanting differ- ent options, could potentially spur progress of the immunocontraceptive approach. The Alliance for Microbicide Development could serve as an instructive model in that regard. Other targets and formulations for contraceptive vaccines are also under investigation, but thus far, proof of concept has not been firmly established (reviewed by Gupta, 2003~. Because immunocontraception could provide an alternative and novel method of fertility regulation, funding should be made available to establish proofs of concept for the most advanced and promising leads, based on sound science, to move the field forward. Examples include sperm surface antigens and epididymal carbohydrate antigens, as well as antigens known to induce immune responses in infertile couples (see the section on proteomics in Chapter 2 for more detail). In the ovum, the oolemma (vitelline membrane) might also be a viable target, although little is known about the oolemma, and such research would be at a much earlier stage than the stages of the approaches noted above. One challenge for these alternate approaches is accurate assessment of the immune status of those vaccinated. If antibodies are raised to inhibit

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98 NEW FRONTIERS IN CONTRACEPTIVE RESEARCH circulating hormones such as hCG, measurement of the antibody levels is meaningful, but when the level of antibody needs to be high in the fallo- pian tube, uterus, or even epididymis, the validity of such measurements is questionable. Experiments with one sperm antigen, sperm-specific LDH-C4, with baboons (both male and female), in which some protection against pregnancy was achieved, there was no relationship between cir- culating antibody levels and fertility status (Mahony et al., 2000; O'Hern et al., 1995~. In addition, a similar lack of correlation between antibody levels and fertility status has been seen in macaque monkeys (Tollner et al., 2002~. In ongoing trials of sperm antigen vaccines, antibody levels will be measured in the female reproductive tract secretions, followed by fer- tility studies with monkeys after active immunization (primary injection with two boosts). Some have also raised ethical considerations about contraceptive vac- cines. For example, an anti-hCG vaccine would block the establishment of pregnancy after fertilization, and thus is viewed unfavorably by some as an abortifacient rather than a contraceptive. In addition, following the Indian clinical trial, some women's groups expressed concern that this method could be used to sterilize women without their knowledge or that it could be administered along with routine vaccinations without their knowledge. It is imperative that consumers be involved in the continuing development of such immunocontraceptives to provide knowledge and reassurance. Good science alone is not enough to ensure uptake of such a method. Creative introduction strategies will be critical to ensure the widespread acceptance of such new contraceptive methods once an effec- tive and safe vaccine is obtained. The lack of funding for translational research to move promising leads from proof of concept to a product is a major impediment, but the lack of papers on immunocontraception at annual meetings of major scientific societies also indicates a waning interest in the field. A helpful means of reenergizing the field would be the establishment of an annual immuno- contraceptive workshop, modeled after the ovarian or testis workshops. NICHD could play a leading role in the organization and funding of such an undertaking. REFERENCES Aitken RJ. 2002. Immunocontraceptive vaccines for human use. J Reprod Immunol 57~1- 2):273-287. Amaral E, Faundes A, Zaneveld L, Wailer D, Garg S. 1999. Study of the vaginal tolerance to Acidform, an acid-buffering, bioadhesive gel. Contraception 60~6~:361-366. Bebb RA, Anawalt ED, Christensen RB, Paulsen CA, Bremner WJ, Matsumoto AM. 1996. Combined administration of levonorgestrel and testosterone induces more rapid and effective suppression of spermatogenesis than testosterone alone: a promising male contraceptive approach. J Clin Endocrinol Metab 81~2~:757-762.

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APPENDIX A 201 Sivin I, Diaz S. Croxatto HE, Miranda P. Shaaban M, Sayed EH, Xiao B. Wu SC, Du M, Alvarez F. Brache V, Basnayake S. McCarthy T. Lacarra M, Mishell DR Jr, Koetsawang S. Stern J. Jackanicz T. 1997. Contraceptives for lactating women: a comparative trial of a progesterone-releasing vaginal ring and the copper T 380A IUD. Contraception 55(4):225-232. Snow RC, Guzman Garcia S. Kureshy N. Sadana R. Singh S. Becerra Valdivia M, Lancaster S. Hoffman M, Aitken I. 1997. Attributes of contraceptive technology: women's prefer- ences in seven countries. In: Sundari Ravindran TK, Berer M, Cottingham J. eds. Beyond Acceptability: Users' Perspectives on Contraception. London, UK: Reproductive Health Matters for the World Health Organization. Pp. 36-48. Spitz IM, Croxatto HB, Robbins A. 1996. Antiprogestins: mechanism of action and contra- ceptive potential. Annu Rev Pharmacol Toxicol 36:47-81. Stratton P. Hartog B. Hajizadeh N. Piquion J. Sutherland D, Merino M, Lee YJ, Nieman LK. 2000. A single mid-follicular dose of CDB-2914, a new antiprogestin, inhibits folliculogenesis and endometrial differentiation in normally cycling women. Hum Reprod 15~5~:1092-1099. Swerdloff RS, Bagatell CJ, Wang C, Anawalt BD, Berman N. Steiner B. Bremner WJ. 1998. Suppression of spermatogenesis in man induced by Nal-Glu gonadotropin releasing hormone antagonist and testosterone enanthate (TE) is maintained by TE alone. J Clin Endocrinol Metab 83~10~:3527-3533. Talwar GP, Singh O. Pal R. Chatterjee N. Sahai P. Dhall K, Kaur J. Das SK, Suri S. Buckshee K, et al. 1994. A vaccine that prevents pregnancy in women. Proc Natl Acad Sci U S A 91(18):8532-8536. Task Force on Postovulatory Methods of Fertility Regulation. 1999. Comparison of three single doses of mifepristone as emergency contraception: a randomised trial. Task Force on Postovulatory Methods of Fertility Regulation. Lancet 353~9154~:697-702. Tollner TL, Overstreet JW, Branciforte D, Primakoff PD. 2002. Immunization of female cynomolgus macaques with a synthetic epitope of sperm-specific lactate dehydrogenase results in high antibody titers but does not reduce fertility. Mol Reprod Dev 62~2~:257- 264. Trussell J. Vaughan B. 1999. Contraceptive failure, method-related discontinuation and resumption of use: results from the 1995 National Survey of Family Growth. Fam Plann Perspect 31~2~:64-72, 93. van der Spoel AC, Jeyakumar M, Butters TD, Charlton HM, Moore HD, Dwek RA, Platt FM. 2002. Reversible infertility in male mice after oral administration of alkylated imino sugars: a nonhormonal approach to male contraception. Proc Natl Acad Sci U S A 99(26):17173-17178. Waites GM. 2003. Development of methods of male contraception: impact of the World Health Organization Task Force. Fertil Steril 80~1~:1-15. Weston GC, Schlipalius ML, Bhuinneain MN, Vollenhoven BJ. 2002. Will Australian men use male hormonal contraception? A survey of a postpartum population. Med J Aust 176~5~:208-210. World Health Organization. 1975. Development of Vaccines for Fertility Regulation, WHO Sponsored Session of the Third International Symposium on Immunology of Reproduction, Varna. Copenhagen: Sciptor. World Health Organization Task Force on Methods for the Regulation of Male Fertility. 1990. Contraceptive efficacy of testosterone-induced azoospermia in normal men. Lancet 336~8721~:955-959. World Health Organization Task Force on Methods for the Regulation of Male Fertility. 1996. Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men. Fertil Steril 65~4~:821-829.