In May 1999, a Licensing Agreement between Zonagen, Inc. and the NICHD was finalized to develop new 19-substituted-norprogestins. If the new antiprogestins behave as tissue-specific modulators in the manner of selective estrogen response modulators (SERMs), they may be recognized as an analogous class of drugs, i.e., as SPRMs. Such SPRMs discovered by NICHD and realized as drugs through this SBIR, would bring the results of government-sponsored science into the public domain. We expect that the new generation of compounds will be used for a number of indications where the etiology is dominated by progesterone. Tissues of the reproductive system such as pituitary, breast, myometrium, cervix, and endometrium remain obvious target organs for treatment. Their potential for use in labor and delivery and in breast cancer remains high. The following document outlines experiments to be performed under Phase II of an SBIR that would clarify the properties of these new SPRMs and enhance their utility for the treatment of endometriosis. It was the intention of Phase I of this SBIR program to determine effects on the eutopic endometrium of cynomolgus monkeys (Macaca fascicularis) following short-term administration, of our lead compound, CDB-4124. We did not believe SPRMs could affect ectopic lesions (endometriosis) if there was no effect on eutopic endometrium. We found that our lead compound had effects on the endometrium similar to RU 486 but without evidence of effects on ovulation and without raising cortisol. We established methods and the baseline levels of markers of inflammation in the peritoneal cavity of the monkey. We intend to expand this program in Phase II to determine whether the same compound will reduce the size of endometriosis-like lesions in the same species. This animal model has been shown to respond to both GnRH agonists and to RU 486 with a decrease in lesion size. The use of GnRH agonists in women for the amelioration of endometriosis, although far from ideal, is one of the few medical therapies currently available. The primary outcome parameters will be alterations in the growth of ectopic endometrium and effects on hormones with our lead antiprogestin compound, CDB-4124. The secondary outcome parameter will be the effects on markers of endometriosis in peritoneal fluid and bone mineral density. The tertiary outcome parameters will be the assessment of the impact of our compound on inflammation markers, on cycling and on liver function.
