Asoprisnil - Phase II in UF, effects on Endo:
Well maybe it's time to talk differentiation between Proellex and Asoprisnil. Below is text from a paper on the Asoprisnil Phase II in UF, describings effects on endometrium (safety, not efficacy).
By-the-way, thnkx not to me but to dewophile who pulled the paper, and who I expect will chime in to point certain things out. Also you wont have to save this post, because it will be referenced in an upcoming RMF edition.
I have broken this into 2 parts, first the detailed stuff, next post will be the Discussion section from the paper. Sorry, I dont have the figures to include.
Overall description of endometrial morphology associated with asoprisnil
Endometrium of patients treated with asoprisnil showed a combination of morphological features affecting glands, stroma and vessels. Although none of these features was on its own specific for asoprisnil, the occurrence of several features together allowed designation of the endometrium as showing the ‘non-physiologic secretory effect’. In this pattern, the endometrial glands showed some features associated with secretory differentiation, often with serpentine or tortuous profiles, composed of columnar epithelial cells with infrequent or absent mitotic activity (see Fig. 1A as an example). However, glands rarely showed any evidence of active secretion, as cytoplasmic vacuolation was absent in most cases. There was a tendency for cystic dilatation of glands, but no abnormal folding patterns or increase in gland-stroma ratio above normal (Fig. 1B). The stroma showed a tendency for increased cellularity without evidence of decidual change. One of the most consistent changes with asoprisnil was the effect on vessels, of which there were two characteristic appearances. First, thick-walled muscularized vessels, similar to those seen in the stroma of the common benign endometrial polyp, were commonly found in the stroma of asoprisnil-treated patients (Fig. 1C), but were not identified in any subjects receiving placebo. Secondly, aggregates of thin-walled vessels were seen at all levels of the endometrium, from within stratum basalis to just beneath surface epithelium (Fig. 1D). These were not specific to asoprisnil, as they were occasionally observed in placebo-treated patients, but they were much more common among asoprisnil-treated patients. In asoprisnil-treated patients, endometrium was commonly thin (Fig. 1D) and frequently it was not possible to distinguish stratum basalis from the stratum functionalis. The morphological features associated with asoprisnil were similar in the thin endometrium of both basalis and functionalis.
Individual features of endometrial glands
With asoprisnil, cytoplasmic secretory vacuolation was relatively infrequent (up to 30%) in patients taking 10 mg, and absent from glands in all locations in all patients taking 25 mg. With asoprisnil, gland architecture varied from simple tubules with minimal undulation to a tortuous appearance resembling that of the mid- or late secretory phase. Simple tubular gland architecture with minimal undulation was more commonly seen in endometrium from the isthmus in patients taking 25 mg (40%) than in fundus or mid-corpus (9%). Asoprisnil 25 mg led to some degree of cystic gland dilatation in all uterine locations but especially in the isthmus (80% compared to 29% with placebo). No differences in the frequency of other glandular architectural abnormalities, such as the abnormal folding patterns seen in the disordered proliferative pattern (Mutter and Ferenczy, 2002DEM026C8 DEM026C8) were identified between asoprisnil-treated patients and controls. The predominant epithelial cell type seen in glands in all locations was comparable between asoprisnil and placebo, consisting of tall columnar cells showing a degree of nuclear stratification that did not vary significantly between treatment groups. Epithelial cell nuclei showed no cytological atypia in any patient. Although a systematic assessment was not performed, histologically there was no apparent difference in numbers of apoptotic glandular cells between asoprisnil-treated patients and controls.
Mitotic activity in endometrial glands and stroma
Mitotic activity for endometrial glands is shown in Table 4 and for stroma in Table 5. As five out of seven, five out of seven and five out of seven samples from placebo-treated patients showed normal secretory endometrial appearances in which mitoses are very infrequent or absent, and only one out of seven, one out of seven and one out of seven specimens showed normal proliferative appearances (Table 3), mitotic activity cannot properly be compared between asoprisnil-treated patients and the placebo group. However, it is notable that in the group of patients treated with 25 mg asoprisnil, no mitotic activity in endometrial glands was identified in any specimen except for one sample of fundic endometrium in one patient. At least 70% of specimens from patients taking 10 mg asoprisnil showed one mitosis or less per 10 high-power fields (HPF) in endometrial glands. In endometrial stroma, patients who received 25 mg asoprisnil showed absence of mitotic activity in 8 out of 11, 9 out of 11 and 9 out of 9 assessable slides, and with 10 mg, 1 mitosis or less per 10 HPF was seen in 7 out of 10, 10 out of 10 and 8 out of 10 assessable slides.
Stromal changes
Stromal decidual change was seen around vessels in a specimen from fundus only in one patient taking 25 mg asoprisnil, but in the remaining assessable samples from patients taking either 10 or 25 mg asoprisnil there was no decidual change identified. In contrast, decidual change was present in endometrial stroma in three of seven, three of seven and three of seven samples from patients taking placebo. With asoprisnil, there was an increased frequency of stromal compactness in all uterine locations, compared with placebo. Stroma was assessed as compact in zero of seven, zero of seven and one of seven placebo samples, compared to 6 of 10, 3 of 10 and 3 of 10 samples from patients taking 10 mg asoprisnil and 6 of 11, 5 of 11 and 7 of 10 on 25 mg.
Vessels
Aggregates or leashes of thin-walled vessels were seen with increased frequency in endometrial stroma of asoprisnil-treated patients compared with controls (Table 7). Samples from patients on placebo showed the presence of at least one aggregation of thin-walled vessels in 2 of 7, 1 of 7 and 0 of 7, whereas these were present in 3 of 10, 5 of 10 and 2 of 10 samples from patients on 10 mg asoprisnil and in 5 of 11, 5 of 11 and 4 of 10 on 25 mg.
Thick-walled vessels, similar to those seen in the stroma of endometrial polyps, were seen with increased frequency compared with controls in all uterine locations in patients treated with asoprisnil. Such vessels were not seen in any samples from placebo subjects, whereas they were found in 2 of 10, 3 of 10 and 1 of 10 samples from patients on 10 mg asoprisnil and in 5 of 11, 5 of 11 and 3 of 10 on 25 mg.
Although there are some similarities, the changes associated with asoprisnil differ from those associated with endometrial polyps. In the latter, thick-walled vessels occur in the stroma of a rounded, projecting polypoid mass in which gland crowding may be observed, and the stroma frequently has a collagenous appearance. After 12 weeks treatment with asoprisnil, gland crowding is not seen, the stroma does not appear prominently collagenized, and the endometrium remains flat and often thinned.
Non-endometrial vascular beds
There were 12 ovaries from eight patients, 15 Fallopian tubes from 10 patients and 10 cervices available for assessment of vascular beds in non-endometrial tissues. No specific histological abnormalities were observed.
Myometrium
Myometrium samples were obtained from all 33 patients and morphological assessments were performed. Adenomyosis was infrequent (present in one control subject, one taking 10 mg and four taking 25 mg asoprisnil). No further abnormalities or changes were identified in these samples.
Leiomyomata
Histological evaluation of the largest leiomyoma of each hysterectomy specimen showed 29 of 30 to be of the usual histological type, and one to be of cellular type. Degenerative changes (hyaline or myxoid/mucoid changes, or coagulative necrosis) were seen in 4 of 9 leiomyomata from the placebo group, 8 of 12 in the 10 mg and 7 of 9 in the 25 mg asoprisnil group. In the placebo group, mitotic activity was not identifiable in one of eight leiomyomata, and in the range 1–2 mitoses per 10 HPF in the remaining seven of eight assessable leiomyomata (Table 8). In the 10 mg asoprisnil group, 8 of 12 showed no identifiable mitoses and 4 of 12 showed 1–2 mitoses per 10 HPF. In the 25 mg asoprisnil group, six of nine showed no mitoses, two cases showed 1–2 mitoses per 10 HPF and one case showed 3–5 mitoses per 10 HPF.
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