Elagolix vs

Dienogest for

EndometriosisHesham Al-Inany, M.D, PhD (Amsterdam)

Outline of this talk

• Introduction

•Elagolix

•Dienogest

Why this talk?

• To update our knowledge

•A real breakthrough in management of endometriosis

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.

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

How to achieve this??

•Dienogest

•Elagolix

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

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.

Animal studies – anti-proliferative effects

• Dienogest reduces endometrial implant volume1,2

.1 Katsuki Y et al. Eur J Endocrinol 1998; 138: 216–226..2 Fischer OM et al. Gynecol Obstet Invest 2011; 72: 145–151 .

Control rat at proestrus stage

Rat given dienogest

Reduction of endometrial implants (cyst walls) in:

Vo

lum

e o

f en

do

met

rial

imp

lan

ts (

mm

3 )

*P<0.05 versus control

)1mg/kg per day(

Control Dienogest

Vo

lum

e o

f en

do

met

rial

imp

lan

ts (

mm

3)

12

Human studiesM

ean

rA

FS

sco

re

rAFS, revised American Fertility Society.

Error bars represent mean ±SEM .

Figure adapted from Köhler G et al. Int J Gynaecol Obstet. 2010; 108: 21–25.

11.4

3.6

p<0.001; Visanne® group

Visanne® significantly reduced mean lesion score

by 7.8 at week 24

Week 0 Week 24

13

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 64Lesion 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 186Strowitzki 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.

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

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.

13

Est

rad

iol

leve

l (p

g/m

L)

mea

n ±

S

EM

Estrad

iol level

(pm

ol/L

) mean

±

SE

M

20

10

70

60

50

40

30

90

80

0

Weeks of treatment0

100- 350

24

Difference statisticallysignificant (P=0.0003)

- 300

- 150

- 0

- 100

- 50

- 250

- 200

Dienogest 2 mg Leuprolide acetate

Adapted from Strowitzki T et al. Hum Reprod 2010.

Weeks of treatment

%ch

ange

in B

MD

bone mineral density

Strowitzki T et al. Hum Reprod 2010;25:633–641.

Visanne®

19

Bone mineral density did not decrease during 24 weeks of treatment with Visanne®

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

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.

Elagolix

•GnRH antagonist

• Immediate action

•Rapid reversible

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

Elagolix

• small molecule, non-peptide GnRH antagonists

• therefore can to be administered orally.

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.

Clinical trials

• 15 registered

• 14 company sponsored

•Only on patients with laparoscopically proven endometriosis

Aim

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

Compared to

•S.C depo medroxyprogesterone acetate (SC-DMPA) administered every three months

•Duration 6 month only

Follow up

• for 6 month after end of the study

•Visual Analogue Scale (VAS)

•Composite Pelvic Signs and Symptoms Scale (CPSSS)

•DEXA

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.

S.E : 10%

•Hot flushes

•Headeche

• nausea

Menses

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

BMD !!!!!

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

Major benefits

•No contraindications (CVS, DVT)

•NO menstrual irregularities

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.

Future use? : needs trials!!

• uterine fibroids

• prevention of premature LH surge in IVF cycles

• steroid-dependant malignancies such as prostate cancer.

So

Dienogest

•Effective

•Up to 2 yrs

•Menstrual irregularities

• contraindications

Elagolix

•Seems effective

•Up to 6 month

•BMD

•No reported contraindications

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

Thank youDr. Hesham Al-Inany MD, PhD

e-mail : kaainih@yahoo.com