Dienogest For Treatment of Endometriosis

Declaration

• No conflict of interest at all with this product or the manufacturing company

Why this talk?

• To update our knowledge• A real breakthrough in management of

endometriosis

• To share

Treatment of Endometriosis

• Treatment could be surgical or medical • Combined• There is no permanent cure !!!

Q1: What is the problem

• Endometriosis has high rate of recurrence up to 60% within 5 years of surgery

Ideal Goal

• As stated by the ASRM, “Endometriosis should be viewed as a chronic disease that requires a life-long management plan with the goal of maximizing the use of medical treatment and avoiding repeated surgical procedures.” Fertil & Steril, 2008

Q2: How to prevent recurrence?

• GnRH agonist• Progestin• others

GnRHa

• Effective • Severe hypoestrogenic state• Limited to 6 month• Bone loss

Progestins

• effective in endometriosis only at high doses• This may increase the likelihood of adverse

effects, such as weight gain and androgenic effects

• may elevate the risk of CVS adverse events

Dienogest (Visanne)

• is a synthetic oral progestogen with unique pharmacological properties

• highly selective for the progesterone receptor

Unique

• strong progestational effects • moderate antigonadotrophic effects

•no androgenic, glucocorticoid or mineralocorticoid activity.

Administration

• 2mg once-daily• Can start at any day of menstrual cycle• Must be continued regardless of vag. Bleeding

Dose

• it appears that at a dose of 2 mg dienogest per day, ovulation is inhibited but ovarian hormone production is not completely suppressed.

• Thus, compared to other endometriosis treatments, estrogen-deficiency related side effects are expected to be of low intensity with 2 mg dienogest.

For How Long?

• Based on Its relatively short half-life of 10 hours means that there is no risk of accumulation after repeated dosing.

• Suggested for long term treatment

License

• An EU marketing authorisation application for the use of dienogest to treat endometriosis was granted by The Netherlands in December 2009.

Where is the evidence?

• There are a number of studies comparing dienogest treatment with buserelin (double-dummy), and triptorelin (open-label), and one longer-term study.

• Some of these studies have been carried out in Japanese, not European, women.

• None of these were sponsored by Bayer.

Pivotal study

• The safety and efficacy of dienogest 2mg daily for 12 weeks was assessed in 198 women with endometriosis and pain above 30mm on a visual analogue scale (VAS), in a randomised, placebo-controlled study. (Strowitzki et al, 2010)

Results

• Reductions on the VAS in endometriosis-associated pelvic pain (the primary endpoint) were 27.4mm with dienogest and 15.1mm with placebo, (mean difference in core of 12.3mm; 95% CI 6.4 to 18.1, p<0.0001).

• 168 women have continued with a further 52 weeks of dienogest treatment

Long term study

• open-label extension study of dienogest for up to 52 additional weeks, providing an overall treatment period of up to 65 weeks. (~ 5 yrs)

Results

• The 52-week extension study results showed a progressive reduction in the frequency of and improvements in endometriosis-associated pelvic pain scores.

Surrogate outcomes

• During the long-term study, laboratory parameters, vital signs, and body weight remained stable or underwent minimal changes.

• Adverse effects considered potentially treatment-related developed in 16.1% of women, including breast discomfort (4.2%), nausea (3.0%), and irritability (2.4%).

SE

• The most commonly reported treatment-related adverse event was metrorrhagia (71.9%), followed by headaches (18.5%) and constipation (10.4%). None of the treatment-related adverse events was rated as serious

Comparison with leuprorelin

• Dienogest 2mg/day (n=124) was compared with leuprorelin 3.75mg/4 weeks (n=128) in a randomised 24- week study.

• Improvements in VAS scores of endometriosis-associated pelvic pain were similar in both groups (reductions of 47.5mm with dienogest and 46.0 with leuprorelin)

Comparison with intranasal buserelin

• In Japan, a Phase III, randomized, double-blind, multicenter, controlled trial was conducted to compare the efficacy and safety of DNG with intranasal buserelin acetate in patients with endometriosis.

VAS at 24 ws

• In both groups the change was large enough to be clinically relevant. For the objective symptoms, the change was from 3.8±2.1 to 1.9±1.9 in the dienogest group and from 3.7±2.0 to 1.5±1.3 in the buserelin group (difference of mean change -0.35, 9% CI -0.75 to 0.05).

Moreover

• The study demonstrated that DNG causes less bone mineral density loss, resulting in the use on a commercial basis for endometriosis patients in Japan from 2008. (Momoeda et al, 2009)

Comparison with triptorelin

• Dienogest 2mg/day (n=59) was compared with triptorelin 3.75mg/4 weeks (n=61) in an open-label 16-week study. Patients had undergone an operative laparoscopy and drug treatment was used as consolidation therapy.

Results

• No reappearance of endometrial tissue was achieved in 25% of patients in each group.

• 86.2% of patients treated with dienogest and 80% of patients treated with triptorelin were satisfied with treatment.

• Fifteen patients in the dienogest group and 12 in the triptorelin group had spontaneous pregnancies in the 12 months following the end of treatment, p=0.71

Potential benefits over existing technologies

• Dienogest appears to be safe and effective when taken for up to 2 years. Current treatments are limited to shorter treatment intervals.

• Dienogest is an oral therapy• Treatment of endometriosis with dienogest is

not inferior to that with GnRH agonists.

Contraindications (CVS & liver)

• DVT• Arterial and cardiovascular disease, past or

present (e.g. myocardial infarction, cerebrovascular accident, ischemic heart disease)

• Presence or history of severe hepatic disease as long as liver function values have not returned to normal

• Presence or history of liver tumours (benign or malignant)

Limitations

• Uterine bleeding may be aggravated with the use of Visanne®.

• Longer-term treatment (up to a year) is required before a positive effect on the number and duration of days/ episodes of bleeding or spotting (a reduction) can be seen.

Ovulation inhibition

• doses ≥1 mg dienogest per day inhibited ovulation. However, follicular maturation processes evident by a rise in serum estradiol levels were not completely suppressed even with the highest dose of 2 mg dienogest.

Share : Meta-analysis

Absolute reduction in VAS

Mean Difference (IV, Fixed, 95% CI)

-1.60 [-9.17, 5.97]

Proportion of women experienced improvement in VAS

Odds Ratio (M-H, Fixed, 95% CI)

1.26 [0.27, 5.80]

SE

Alopecia Odds Ratio (M-H, Fixed, 95% CI)

0.60 [0.17, 2.09]

Migraine Odds Ratio (M-H, Fixed, 95% CI)

0.52 [0.13, 2.13]

Sleep disorder Odds Ratio (M-H, Fixed, 95% CI)

0.20 [0.04, 0.93]

Vaginal dryness Odds Ratio (M-H, Fixed, 95% CI)

0.22 [0.05, 1.06]

Hot flushes Odds Ratio (M-H, Fixed, 95% CI)

0.40 [0.25, 0.65]

Abnormal genital Bleeding Odds Ratio (M-H, Fixed, 95% CI)

8.41 [3.60, 19.63]

Others

Decreased Libido Odds Ratio (M-H, Fixed, 95% CI)

0.65 [0.21, 2.05]

Depression Odds Ratio (M-H, Fixed, 95% CI)

0.56 [0.20, 1.56]

weight gain Odds Ratio (M-H, Fixed, 95% CI)

1.76 [0.56, 5.53]

Headache Odds Ratio (M-H, Fixed, 95% CI)

0.62 [0.40, 0.95]

More to Share: RCTs

• Dienogest in endometriosis associated Infertility: Visanne for 3 month Then clomid vs clomid alone

• Dienogest associated menstrual irregularities: Visanne with Cycloprogenova for the first 3 month vs Visanne alone

Conclusion

• DNG represents a promising new medication for safe and effective long-term management of pain of endometriosis.