Elagolix is a new drug for endometriosis. What are its advantages and sideeffects? this talk may shed some light on this

1. Elagolix
vs
Dienogest
for
Endometriosis
Hesham Al-Inany, M.D, PhD
(Amsterdam)

2. Outline of this talk
• Introduction
• Elagolix
• Dienogest

3. Why this talk?
• To update our knowledge
• A real breakthrough in management
of endometriosis

4. Changing trend
• orally administered drugs
• more convenient
• avoidance of injection site reactions
• more practical way to take advantage
of the drug’s dose-response curve to
optimize the risk-benefit ratio.

5. Q1: What is the problem
• Endometriosis has high rate of
recurrence up to 60% within 5 years
of surgery

6. 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

7. How to achieve this??
• Dienogest
• Elagolix

8. Dienogest (Visanne)
• is a synthetic oral progestogen with
unique pharmacological properties
• highly selective for the progesterone
receptor

9. Unique
• strong progestational effects
• moderate antigonadotrophic effects
•no androgenic, glucocorticoid or
mineralocorticoid activity.

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

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

12. Animal studies – anti-proliferative effects
• Dienogest reduces endometrial implant volume1,2
Reduction of endometrial implants (cyst walls) in:
Control rat at proestrus stage Rat given dienogest
Control Dienogest
Katsuki Y et al. Eur J Endocrinol 1998; 138: 216–226. .1
Fischer OM et al. Gynecol Obstet Invest 2011; 72: 145–151. .2
Volume of endometrial implants (mm3)
*P<0.05 versus control
(1mg/kg per
day)
Volume of endometrial implants (mm3)
12

13. Human studies
Mean rAFS score
p<0.001; Visanne® group
3.6
reduced mean lesion score
Week 0 Week 24
rAFS, revised American Fertility Society.
Error bars represent mean ±SEM.
11.4
Visanne® significantly
by 7.8 at week 24
Figure adapted from Köhler G et al. Int J Gynaecol Obstet. 2010; 108: 21–25.
13

14. 14
Where is the evidence for
clinical efficacy?
Study type Study
duration
Sample size
(n)
Main efficacy
end-points
Publication
Open-label dose-range
finding
24-week 64
Lesion reduction
rAFS score with 2nd look
laparoscopy
Köhler et al. (2010)
Placebo-controlled double-blind
12-week 198
Pain relief: VAS
Strowitzki et al. (2010)
Open-label extension of
placebo-controlled study
53-week 168 Petraglia et al. (2012)
Open-label leuprolide
acetate- controlled
24-week 186
Strowitzki et al. (2010)
Strowitzki et al. (2012)
rAFS=revised American Fertility Society; VAS=visual analog scale.
Köhler G et al. Int J Gynaecol Obstet 2010; 108: 21–25.
Strowitzki T et al. Eur J Obstet Gynecol Reprod Biol 2010;151:193–198.
Petraglia F et al. Arch Gynecol Obstet 2012; 285(1):167‒173.
Strowitzki T et al. Hum Reprod 2010; 25: 633–641.
Strowitzki T et al. Int J Gynecol Obstet 2012; 117: 228–233.

15. 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

16. Potential benefits over
existing technologies
• Dienogest appears to be safe and
effective when taken for up to 2 years.
• Treatment of endometriosis with
dienogest is not inferior to that with
GnRH agonists.

17. 13
Estradiol level (pg/mL)
mean ± SEM
Estradiol level (pmol/L)
mean ± SEM
90
80
70
60
50
40
30
20
10
0
Weeks of treatment
0
100
- 350
24
- 300
- 250
- 200
- 150
- 100
- 50
- 0
Difference statistically
significant (P=0.0003)
Dienogest 2 mg
Leuprolide acetate
Adapted from Strowitzki T et al. Hum Reprod 2010.

18. Weeks of treatment
% change in BMD
bone mineral density
Visanne®
Strowitzki T et al. Hum Reprod 2010;25:633–641.
19
Bone mineral density did not decrease during 24 weeks of treatment with Visanne®

19. 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

20. 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.

21. Elagolix
• GnRH antagonist
• Immediate action
• Rapid reversible

22. Proteolysis
• Currently available GnRH antagonists
are all peptide analogues of the GnRH
and therefore cannot be taken orally
as the protein structure of the
molecule undergoes proteolysis in the
GI tract before absorption

23. Elagolix
• small molecule, non-peptide GnRH
antagonists
• therefore can to be administered
orally.

24. Pharmacodynamics
• Elagolix causes a rapid, dose-dependent
suppression of pituitary
gonadotropins, mainly LH and to a
lesser extent FSH,
• reaching its peak effects 4-6 hrs after
oral administration.

25. Clinical trials
• 15 registered
• 14 company sponsored
• Only on patients with laparoscopically
proven endometriosis

26. Aim
• To evaluate the efficacy and safety of
GnRH antagonists for the treatment of
endometriosis related pain

27. Compared to
• S.C depo medroxyprogesterone
acetate (SC-DMPA) administered
every three months
• Duration 6 month only

28. Follow up
• for 6 month after end of the study
• Visual Analogue Scale (VAS)
• Composite Pelvic Signs and
Symptoms Scale (CPSSS)
• DEXA

29. Results : it works
• significant improvment compared to
the baseline, with the majority of
patients continuing to report beneficial
effects at 6 months after completion of
the study.

30. S.E : 10%
• Hot flushes
• Headeche
• nausea

31. Menses
• About 25% of patients on Elagolix
developed amenorrhea within 8-week
period of administration

32. BMD !!!!!
• significant reduction in BMD at the
spine after 12 weeks, and at spine
and femur after 24 weeks.

33. Major benefits
• No contraindications (CVS, DVT)
• NO menstrual irregularities

34. Phase III trials
• Currently 2 phase III trials
• sponsored by Abbvie Pharmaceutical
Inc.
• Aiming to recruit 875 patients in US,
Canada and Puerto Rico, comparing
the effects of two different Elagolix
regimens (150 vs 250mg) for 6
months.

35. Future use? : needs trials!!
• uterine fibroids
• prevention of premature LH surge in
IVF cycles
• steroid-dependant malignancies such
as prostate cancer.

36. So
Dienogest
• Effective
• Up to 2 yrs
• Menstrual
irregularities
• contraindications
Elagolix
• Seems effective
• Up to 6 month
• BMD
• No reported
contraindications

37. Conclusion
• It seems that the age of injections is
fading away
• Orally administered medications for
endometriosis is now a reality
• Individualisation will be the basis for
choosing either dienogest vs Elagolix

38. Thank you
Dr. Hesham Al-Inany MD, PhD
e-mail : kaainih@yahoo.com