Multicenter phase II study: investigational drug treats fibroid-related bleeding

OB/GYN News, May 15, 2004 by Betsy Bates

HOUSTON -- The investigational selective progesterone receptor modulator asoprisnil induced amenorrhea or normal menstrual periods in a clear majority of women with myoma-associated menorrhagia in a multicenter phase II study.

"In subjects with uterine fibroids, asoprisnil rapidly suppressed both the duration and intensity of uterine bleeding without inducing unscheduled bleeding," Dr. Kristof Chwalisz reported during the annual meeting of the Society for Gynecologic Investigation.

"Hemoglobin [concentrations] increased significantly at all treatment doses," stated Dr. Chwalisz, a research scientist for TAP Pharmaceutical Products, Lake Forest, Ill., which sponsored the study.

Asoprisnil, formerly known as J867, is currently in yearlong, phase III trials and holds the promise of becoming the first medical treatment approved for uterine fibroids.

Phase II trial results that were released a year ago demonstrated a reduction in both symptoms and uterine fibroid size.

Bleeding patterns and hemoglobin levels were the focus of a more recent analysis of the phase II, randomized, double-blind, placebo-controlled, parallel group study.

In this analysis, bleeding diaries kept over the course of 3 months showed a "dramatic," dose-dependent reduction in spotting and bleeding among 129 women aged 18-49 who had large ([greater than or equal to] 3 cm) symptomatic uterine fibroids.

The subjects were asked to assess their bleeding according to a rating system, with "0" representing normal menstrual bleeding and no spotting and "4" representing heavy bleeding, defined as using more than four tampons or pads in 24 hours. These daily scores were totaled and divided by the number of days of bleeding during the study to obtain the average daily score. This number was then multiplied by 28 to get the average monthly score.

Subjects who were using this system were randomly assigned to 25 mg of asoprisnil averaged a score of 1.3, compared with 4.7 for those taking 10 mg, 7.3 for those taking 5 mg, and 15.6 for subjects assigned to placebo.

Menorrhagia, which was present in 98 of 129 patients at baseline, improved dramatically, with every subject taking the 25-mg dose reporting normal or absent periods by month 3 of the study.

In dose-dependent fashion, 14 of 16 menorrhagic women who were on the 10-mg dose had normal or absent periods by the study's conclusion, compared with 18 of 23 taking 5 mg.

Among the 21 menorrhagic women assigned to placebo at baseline, just 5 had absent or normal periods by month 3.

"This effect was very rapid, so that at week 4 there was a substantial reduction at all doses of bleeding intensity and a reduction in menorrhagia scores," Dr. Chwalisz said at the meeting.

Endometrial biopsies demonstrated clusters of thick-walled, spiral vessels in the functionalis of subjects who received asoprisnil, but no hyperplasia, suggesting that the endometrial vasculature is the primary target of the drug, he explained.

As a selective progesterone receptor modulator, asoprisnil has an agonist/antagonist effect on progesterone receptors, with a high degree of tissue selectivity. It has an antiproliferative effect on the endometrium without suppressing ovarian estrogen production.

BY BETSY BATES

Los Angeles Bureau