Clinical uses of selective progesterone modulators

Anna GlasierUniversity of Edinburgh

Ulipristal Acetate

Clinical uses of selective progesterone receptor modulators

• Induction of Abortion• Emergency Contraception• Management of Leiomyoma

Clinical uses of selective progesterone receptor modulators

• Induction of Abortion• Emergency Contraception• Management of Leiomyoma

Progesterone is essential for the establishment and maintenance of

pregnancy

Mifepristone

• Synthesised 1980 Roussel-Uclaf in France (RU 38,486)• Increases uterine contractility & sensitizes uterus to PGs• Tested as abortifacient in 1981 Geneva (Hermann)• Approved in France in 1988, UK 1991, Sweden 1992• Approved in USA in 2000• Now licensed in more than 40 countries for medical

abortion• In USA in 2008 25% of abortions < 9 weeks by MA• In Scotland in 2012 86% of abortions < 9 weeks by MA

www.who.int/reproductivehealth/publications/unsafe_abortion/9789241548434/en/index.html

http://www.rcog.org.uk/files/rcog-corp/Abortion%20guideline_web_1.pdf

7.18

Medical abortion regimens using 200 mg oral mifepristone and misoprostol are effective and appropriate at any gestation.

Concept Foundation

Approved in 14 countries in EuropeAlso now in Cambodia,Ghana, India, Kenya, Mozambique, Nepal and Zambia at about US$3.5

Clinical uses of selective progesterone receptor modulators

• Induction of Abortion• Emergency Contraception• Management of Leiomyoma

Emergency Contraception Methods

• High dose estrogen (1963) • Estrogen and progestogen (1972)• Copper IUD up to 5 days after ovulation (1976)• Levonorgestrel (1970s,1999)• Mifepristone (China,Russia, Ukraine) (1991)• Ulipristal acetate (2006)

Comparison of three single doses of mifepristone as emergency contraception: a randomised trial.

WHO Task Force on Post-Ovulatory Methods of Fertility Regulation. Lancet 1996

• RCT in 1717 women - up to 5 days after IC • Mifepristone (600 mg, 50 mg, and 10 mg) • Pregnancy rates 1.1 - 1.3% no differences

Low dose mifepristone and two regimens of levonorgestrel for emergency contraception: a WHO

multicentre randomised trial.

WHO Task Force on Post-Ovulatory Methods of Fertility Regulation. Lancet 2002

• RCT in 4000 women up to 5 days after IC• LNG versus 10mg mifepristone• 10mg mifepristone as effective as LNG

Ulipristal acetate

A second generation progesterone receptor modulator with little anti-glucocortioid activity

specifically developed for emergency contraception

UPA LNG OR

Creinin0-72h

7/773 13/7730.5

(0.18-1.24)

Ulipristal acetate versus levonorgestrel for EC: a randomised non‐inferiority trial and meta‐analysis.

UPA LNG OR

Creinin0-72h

7/773 13/7730.5

(0.18 -1.24)Glasier 0-120h

15/941 25/9580.57

(0.29 -1.09)

Ulipristal acetate versus levonorgestrel for EC: a randomised non‐inferiority trial and meta‐analysis.

UPA LNG OR

Creinin0-72h

7/773 13/7730.5

(0.18 -1.24)Glasier 0-120h

15/941 25/9580.57

(0.29 -1.09)Meta-analysis 0-24h

5/548 15/6000.35

(0.11 - 0.93)Meta-analysis 0-72h

22/1617 35/16250.58

(0.33 - 0.99)Meta-analysis 0-120h

22/1714 38/17310.55

(0.32 - 0.93)

Ulipristal acetate versus levonorgestrel for EC: a randomised non‐inferiority trial and meta‐analysis.

Ovulation as measured by ultrasound and pituitary-ovarian function after taking EC

• Croxatto et al Contraception 2004;70: 442– 450• Massai et al Human Reproduction 2007;22: 434–439• Brache et al Human Reproduction 2010; 25: 2256–2263

Ovulation as measured by ultrasound and pituitary ovarian function after taking EC

• EC given to normal volunteers at a specific time of cycle in relation to ovarian follicle size

• Ovarian function & ovulation monitored with hormone measurements

• Ovulation (follicle rupture) monitored with USS• Results analysed in relation to follicle size and timing of

LH surge• Outcomes ovulation, anovulation & ovulatory dysfunction• Yuzpe; LNG (0.75X2 and 1.5mg); LNG + meloxicam;

UPA

Ulipristal acetate prevents ovulation more effectively than levonorgestrel:analysis of pooled data from three

randomized trials of emergency contraception regimens

Brache V, Cochon L, Deniaud M, Croxatto HB.(Contraception 2013;88:611-8.)

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Proportion of cycles with no follicular rupture at day 5 after Rx according to LH levels at Rx

0%

10%4%

25%

14%9%

100%

79%

8%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Tx before LH surge Tx after LH surge butbefore LH peak

Tx at LH peak

PBO (n=50)

LNG (n=48)

UPA (n=34)

ellaOne®30 mg ulipristal acetate

For use up to 120 hours (5 days)

EU marketing authorization granted May 2009

Launched in USA January 2011

Now licensed in 67 countries

ellaOne®Over 1.3 million courses used

Minimal side effects

No attributable SAEs reported

No increase in risk of miscarriage

No increase in risk of ectopic pregnancy

No increase in the risk of fetal malformation

Clinical uses of selective progesterone receptor modulators

• Induction of Abortion• Emergency Contraception• Management of Leiomyoma

UPA versus placebo for fibroid treatment before surgery

(Donnez et al NEJM 2012)

• Women with fibroids, HMB and anaemia• Randomized to UPA 5mg,UPA 10mg or placebo• Treated for 13 weeks• All received iron supplements

UPA versus placebo for fibroid treatment before surgery

(Donnez et al NEJM 2012)

Outcome UPA 5 mg

UPA 10 mg

Placebo

Bleeding controlled (%)

91 92 19

Amenorrhoea (%) 72 82 6

Change in fibroid volume (%)

-21 -12 +3

Donnez et al NEJM 2012

UPA versus leuprolide acetate for fibroid treatment before surgery

(Donnez et al NEJM 2012)

• Women with fibroids, HMB and anaemia• Randomized to UPA 5mg, UPA 10mg or LA

3.75mg• Treated for 13 weeks

UPA versus leuprolide acetate for fibroid treatment before surgery

(Donnez et al NEJM 2012)

Outcome UPA 5 mg

UPA 10 mg

LA3.75mg

Uterine bleeding controlled (%)

90 98 89

Median time to amenorrhoea (Days)

7 7 21

Hot flushes moderate/severe (%)

11 10 40

Gaps in research

• SPRMs as ongoing contraceptives• Effect of SPRMs on the breast

– Treatment of cancer– Prevention of cancer

1994 ICPD plan of action

Governments should ‘meet the family planning needs of their populations as soon as possible and should, in all cases by the year 2015, seek to provide universal access to a full range of safe and reliable family planning methods’

1994 ICPD plan of action

Governments should ‘meet the family planning needs of their populations as soon as possible and should, in all cases by the year 2015, seek to provide universal access to a full range of safe and reliable family planning methods’

‘Addressing this challenge seems a highly cost effective way of addressing many of the world’s problems.’All Party Parliamentary Group on Population, Development and Reproductive Health UK 2007.

Stern Review on the Economics of Climate Change 2006

• All countries will be affected by climate change, but the poorest countries will suffer earliest and most.

• Average temperatures could rise by 5C from pre-industrial levels if climate change goes unchecked.

• Warming of 3 or 4C will result in many millions more people being flooded. By the middle of the century 200 million may be permanently displaced due to rising sea levels, heavier floods and drought.

• Warming of 4C or more is likely to seriously affect global food production.

• Population movement and growth will often exacerbate the impacts by increasing society’s exposure to environmental stresses (for example, more people living by the coast) and reducing the amount of resource available per person (for example, less food per person and causing greater food shortages).

Conclusions• SPRMs are highly effective as emergency

contraceptives, for inducing abortion and for managing fibroids

• They undoubtedly have great potential as regular contraceptive methods

• They should be investigated enthusiastically for treatment and prevention of breast cancer

• Use of SPRMs for regulating reproduction prevents unintended pregnancy thereby helping to protect the environment from over-population and the over-consumption that goes with it.