Recent advances in stimulation protocols

“Understanding Infertility” – New Delhi, India – August 2011 Recent Advances in Stimulation ProtocolsEsteves, 1

1. Present an evolution perspective of gonadotropins 2. GnRH analogues for controlled ovarian stimulation (COS) 3. Protocols for COS: taking advantage of new productsEsteves, 2

Esteves, 3

Patients Doctors Industry

600,000 120,000 Worldwide urine quantity (1000 litres) Number of donors 600 120 1965 1975 1985 1990 1995 2000 Donors from different regions around the worldEsteves, 6

Up to 65% of couples dropout from IVF without achieving pregnancy before they complete 3 cycles1-5 Reasons1,5,6Psychological burden 49%-26%Prognosis 40%-23% Oocyte retrieval 52% Embryo transfer 29%Cost of treatment 23%-0% Injections 29%Relationship/divorce 15%-9% Physical pain 20%Physical burden 7-6% Blood tests 14% 1. Olivius K t al, Fertil Steril 2004;81:258; 2. Land JA et al, Fertil Steril 1997; 68:278; 3. Schroder AK, et al, RBM Online 2004; 5:600; 4. Osmanangaoglu K et al, Hum Reprod 2002; 17:2655; 5. Rajkhowa M et al, Hum Reprod 2006; 21:358; 6. Brandes M et al, Hum Reprod 2009; 24:3127; 7. Hammarberg K et al, Hum Reprod 2001; 16:374.

Typical Cycle (long protocol): Daily SC GnRH-a: x21 FSH/LH: x10-15 hCG: x1 Progesterone: x14 Blood tests: x4-7Number of sticks: 36-57

Gonadotropins: better today Milestones in the development of gonadotrophins 20011940 1962 Full recombinant 2008First hCG 1993 2000 First Purified u-hMG gonadotrophinextracted from First highly purified First r-hLH r-hLH+r-FSH (Pergonal®) and u- portfolio availablehuman urine FSH-only product launched combined hCG (Profasi®) launched (Luveris®) (Pergoveris®) become available (Metrodin HP®) 1949 1980s 1995 2001 2002 First hMG extracted First FSH-only First r-hFSH First r-hCG First filled-by-mass from urine pools product launched launched launched product launched (Metrodin®) (GONAL-f®) (Ovidrel®/Ovitrelle) (GONAL-f® FbM) Milestones in the development of r-hFSH 1980 1983 1985 1988 1992 -subunit -subunit -FSH gene cloned and Human FSH expressed First pregnancy sequenced sequenced expressed in fibroblasts in CHO cells with r-hFSH 1. Bassett et al. Reprod Biomed Online 2005;10:169–177 CHO, Chinese hamster ovary 2. Lunenfeld. Hum Reprod Update 2004;10:453–467

Culture media Bioreactor Harvest Cell attachment and Concentration of proliferation supernatant r-hFSH production and Chromatographic secretion purification steps Collection of cell culture supernatant Ultrasterile filtration medium containing Characterization r-hFSH and full QC of In-process QC bulk r-hFSHEsteves, 10

Gonadotropins: better today Quality Safety Key Clinical issues Efficacy Patient conven- ienceEsteves, 11

From urinary to recombinant Choragon Urinary -hCG from different manufacturers Ferring PregnylOrganon - hMG HP 30% of impurities per vial with 39 different proteins identified (varied from batch to batch) Protein FSH impurities Laboratoire De Spectometrie de MBO – October/2009 van de Weijer et al. Reprod Biomed Online 2003;7:547–557Esteves, 12 Kuwabara Y et al, J Reprod Med 2009; 54:459–466

Impurities cannot be associated with a better or worse outcome but certainly are not needed for COH u-hMG HP Molecular (5 batches) r-hFSH weight (follitropin markers alfa)Esteves, 13 Merck Serono data on file

Australia 1996: Recognizes higher UK 2003: Metrodin HP standards of purity and withdrawn safety of recombinants; unacceptable risks given Encourages their use over that there are alternatives urinary, human derived.Esteves, 14

Purity Mean specific Injected (FSH FSH activity protein content) (IU/mg protein) per 75 IU (mcg) hMG < 5% ~100 ~750* hMG-HP < 70% 2000–2500 ~33* r-hFSH Follitropin beta – 7000–10,000 8.1* Follitropin alfa > 99% 13,645 6.1Esteves, 15 1. Bassett et al. Reprod Biomed Online 2005;10:169–177

Novel analitycal Conventional method Bioassay Physiochemical technique High in vivo variability Minimal batch-to- (rat) batch variability (1.6%)1,2 Urinary gonadotropins Follitropin beta Follitropin alfaEsteves, 16 1. Bassett et al. Reprod Biomed Online 2005;10:169–177; 2. Driebergen et al. Curr Med Res Opin 2003;19:41–46

Concept of Dose PrecisionClinical implications Batch variability Batch variability +20%, -25% 2%IU Risk of OHSS270 16.5 mcg225 (225 IU)170 Poor response Bioassay Filled by Mass Urinary and Follitropin beta Folitropin alfa

Patient Compliancesc rec FSH (pen device)sc rec LHsc hCG (prefilled syringe)

Evidence-based truth: Scientific truth: recFSH is more potent recFSH is purer ↑ 3.1 oocytes (Bosch, 2008) Non urine- extracted product ↑ 1.8 oocytes (MERIT, 2006) Recombinant technology ↑ 2.8 oocytes (Hompes, 2007)Esteves, 19

GnRH analogues in ARTLH surge prevention by GnRH agonists pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2 Activation of the Regulation of Regulation of receptor GnRH receptor receptor affinity biological activity

GnRH analogues in ARTLH surge prevention by GnRH antagonists 1 2 3 pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2 Activation of the Antagonistic Regulation of Regulation of receptor GnRH receptor effect receptor affinity biological activity

LH surge prevention GnRH antagonists Agonist FollicularLH, FSH 30 E2 , P 4 Luteal 20 2-4 weeks 10 Synchronized follicles 0 6 • Half-life ~20h (Cetrorelix) Antagonist 5 • Suppress LH by 80% of 4 baseline levels LH (IU/L) 3 Antagonist 2 1 0 -6 0 6 12 18 24 30 36 42 48 Hours

LH surge prevention GnRH antagonists vs agonists Prevent OHSS Can be integrated by GnRH-a No flare in spontaneous Single or multiple effect with No hormonal and OI cycles Antagonist dose GnRH administration possible cyst withdrawalantagonist protocol formation Gonadotropin administration Less gona- Can exclude dotropins early pregnancy Flare up Pituitary effect suppression Gonadotropin administration Long GnRH agonist protocol Longer Agonist administration treatment Pre-treatment cycle Treatment cycle

Day 1 Rec-hCG Follicle (prefilled syringe) of rFSH 13 mm or GnRH-a rec-FSH (fbm) Individualized rec-FSH dose 112.5-450 UI (recLH supplementation) Vaginal menses progesterone GnRH antagonist Day 2 or 3 0.25 mg/day (flexible) of menses Day 1 Rec-hCG Day 6 (prefilled syringe) of rFSH of rFSH Cycle recFSH (fbm) Individualized rec-FSH dose day 21 112.5-450 UI (rec-LH supplementation) Vaginal progesterone GnRH Agonist menses Day 2-5 of mensesEsteves, 24

Group A (hMG; N=299) Group B (HP-hMG; N=330) Group C (r-hFSH; N=236) Day Day 1 Day 6 of hCG Cycle day 21 Gonadotropin rFSH/hMG Individualized dose 112.5-450 UI Vaginal progesterone Agonist (nasal spray): Nafarelin acetate (400 mcg/day; fixed) mensesEsteves, 25 Day 2-5 of menses

Outcome Measure HMG HP-hMG r-hFSH P- n=299 N=330 n=236 valueTotal gonadotropin dose (IU) 2,685 2,903 2,268 <0.01Retrieved oocytes (N) 10.9 10.7 10.8 NSMII oocytes (N) 8.9 8.9 8.7 NS2PN fertilization rate (%) 72 72 71 NSImplantation rate (%) 24 27 23 NSLive birth rate per cycle (%) 24.4 32.4 30.1 NSModerate/severe OHSS(%) 2.3 1.8 1.3 NS Esteves et al, Reprod Biol Endocrinol. 2009; 7:111

% Cycles with “Step-down”during ovarian stimulation 53.4* *P<0.01 18.7 20.3 HMG HP-HMG rec-hFSH (fbm)

Total Dose per Live Birth (IU)* To achieve a 10.000 live birth, 52.2% 9,690 21-52% more 7.000 21.6% 7,739 HP-hMG and 6,324* hMG was 3.000 required 0 compared with r-hFSH HP-hMG hMG r-hFSH * Mean total dose per cycle/Live birth rate (≤35 years)

Infertility Specialists Gonadotropin Choice in South America? r-hFSH r-hFSH+hMG hMG 1600 1400 1200 Gonadotrophin segment split 1000 (75 IU equivalent units) 800 52% 600 400 200 - 1998 1999 2000 2001 2002 2003 2004 2005 39% Total r-hFSH Total u-FSH Total hMG/LH 9%Esteves, 29 Data supplied by IMS and REDLARA 2007

GnRH antagonists vs agonists Meta-analysis Kolibianakis et al (2006)2 N studies 22 Included non peer-reviewed data No Included IUI cycles No N patients 3176 Odds ratio (probability of live birth) 0.86 (0.72-1.02; p=.08) Duration of stimulation -1.54 days (OR: -2.42; -0.66; p=.0006) Oocytes retrieved -1.19 (OR: -1.82; -0.56) Risk of severe OHSS OR=0.61 (0.42; 0.89; p=.01)* *For every 59 women treated with a GnRH agonist vs GnRH antagonist, one additional case of severe OHSS will occurEsteves, 30

GnRH agonist for triggering oocyte maturation – Humaidan et al Hum Reprod Update 2011  GnRH-a triggering (0.2-1.5 mg): antagonist protocol  Reduced if not eliminated risk for OHSS  In specific high risk patients for OHSS and egg donation programs should become the choice  Challenge is to rescue luteal phase insufficiency  Modified luteal support improved delivery rate hCG bolus OPU day (1,500 UI) or 3x 500 UI boluses; recLH; intense progesterone + estradiol; combined Delivery rates: 18% risk difference favoring hCG (before) X 6% risk (after)Esteves, 31

Esteves, 32

Recent Advances in Stimulation Protocols  Recombinant gonadotropins purer and safer compared to urinary gonadotropins  Recombinant gonadotropins more patient- friendly and have similar (or better) clinical efficacy compared to urinary gonadotropins  COS using GnRH antagonists simplify treatment and decrease OHSS  Novel COS protocols involve recombinant products and GnRH antagonistsEsteves, 33

Recent advances in stimulation protocols

by Sandro Esteves on Aug 10, 2011

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