Menopur ( 美諾孕注射劑 ) 瑞士商輝凌藥品股份有限公司 Brand new, Natural, Three-in-one Gonadotropin

Content Introduction to FSH,LH & HCG Introduction to Menopur Menopur Clinical Study Administration of Menopur

Introduction to FSH,LH & HCG

Introduction to Menopur

Menopur Clinical Study

Administration of Menopur

1. Introduction to FSH,LH & HCG Luteinizing Hormone LH =  +  LH Human Chorionic Gonadotrophin hCG =  +  hCG Follicle Stimulating Hormone FSH =  +  FSH  -subunit provides specificity

LH & HCG 82-83% protein sequence homology (  subunits) HCG can initiate LH action through LH receptors HCG half-life ~24-36 h (LH ~2-10 h )

82-83% protein sequence homology (  subunits)

HCG can initiate LH action through LH receptors

HCG half-life ~24-36 h (LH ~2-10 h )

2. Introduction to Menopur There are FSH , LH , HCG contents in Menopur. Menopur (three-in-one gonadotropin)

There are FSH , LH , HCG contents in Menopur.

LH and hCG Content in Different Commercial Gonadotrophin Drug Products Menopur Pergonal Humegon Gonal-F LH (IU/L) 0.4 13.5 5.8 - hCG (IU/L) 9.9 3.4 6.9 - Wolfenson et al, RBM,10:4, 442-454, 2005

Menopur Pergonal Humegon Gonal-F

LH (IU/L) 0.4 13.5 5.8 -

hCG (IU/L) 9.9 3.4 6.9 -

Each vial of Menopur contains 75 IU of FSH activity and 75 IU of LH activity.( 95% LH activity comes from HCG ) hCG LH

Each vial of Menopur contains 75 IU of FSH activity and 75 IU of LH activity.( 95% LH activity comes from HCG )

Manufacturing of r-FSH rFSH secreted by CHO cell into culture media Crude filtration & clearance Genetically Eng. CHO cells Culturing CHO cells in media with Fetal Bovine Serum (FBS) Cultivating CHO cells in industrial size culturing tanks Immuno chromotographic purification Highly purified material Pharmaceutical Lyophilization & finishing filtrate collected & pooled culture media

Manufacturing of MENOPUR MENOPUR Pooled Post menopausal urine Crude filtration & clearance Screening of eligible health donors Documentation on eligible donors Aseptic Urine collection # Ion exchange chromotographic purification Highly purified material Pharmaceutical Lyophilization & finishing filtrate # Patent technology for purification

Purification Process of Menopur

Purity of Menopur

MENOPUR is a preparation of gonadotropins, extracted from the urine of postmenopausal women

MENOPUR is a preparation of gonadotropins, extracted from the urine of postmenopausal women

HCG in Urine of Normal, Nonpregnant, and Pregnant Individual

HCG in Serum & Urine of Men, Nonpregnant Women

HCG in urine Undetectable in reproductive men and women Marked increase during pregnancy due to high placental production Age-dependent increase Detectable (~3-4 IU/L ) in postmenopausal women 1) HCG occurs naturally in our donors’ urine 2) Ferring does not add HCG to MENOPUR to balance FSH/LH bioactivity

Undetectable in reproductive men and women

Marked increase during pregnancy due to high placental production

Age-dependent increase

Detectable (~3-4 IU/L ) in postmenopausal women

1) HCG occurs naturally in our donors’ urine

2) Ferring does not add HCG to MENOPUR to balance FSH/LH bioactivity

Characteristic of Menopur Subcutaneous / Intramuscular injection FDA approved

Subcutaneous / Intramuscular injection

FDA approved

3. Menopur Clinical Studies

3. Menopur Clinical Studies

Menopur Clinical Study (1) EISG 2002 (The European and Israeli Group on Highly Purified Menoptropin versus Recombinant Follicle-Stimulation Hormone) N = 731

EISG 2002 – Results

Menopur Clinical Study (2) Kilani & Filcori et al., 2003 (Hum Reprod 18:1194-1199) N = 100 Treatment Duration (Days) 8 9 10 11 12 13 14 Menopur rFSH * P <0.05

Menopur Clinical Study (2) Kilani & Filcori et al., 2003 (Hum Reprod 18:1194-1199) N = 100 16 18 20 22 24 26 28 30 Menopur rFSH P <0.05 * GTH used (ampoules)

Menopur Clinical Study (3) EISG 2004 – Retrospective Re-analysis Peter Platteau, 2004 (Fertil Steril 81:1401-4)

EISG 2004 – Result

Menopur Clinical Study (4)

Menopur Clinical Study (5)

MERiT Study ( Menotrophin vs Recombinant FSH in vitro Fertilisation Trial)

Study Protocol N = 731

MERiT Study-Result

Embryo Assessment Criteria Details

MERiT- Echogenic pattern p =0.023 Echogenic pattern 36% 42% Hypoechogenic 49% 48% Isoechogenic 16% 10% Hyperechogenic 10.7 ± 1.9 0.532 97% 96% Triple-layer structure N=368 N=363 0.780 10.8 ± 2.0 Endometrial thickness (mm) P GONAL-F MENOPUR

MERiT Study-Result N = 731

Endocrine Profile – Last Day of Stimulation

MENOPUR treatment resulted in higher E2 serum level, compared to Gonal-F MENOPUR treatment resulted in lower P4 serum level, compared to Gonal-F

MERiT – Results

Ongoing Pregnancy Rate 持續懷孕率 MERiT – Results (96/363) (82/368)

MERiT – Results (44/107) (30/112) (75/396) (72/403) 持續植入率

MERiT – Results (36/75) (24/74) (61/223) (58/229) 持續懷孕率

MERiT – Results Live birth rate (36/75) (24/74) (60/223) (58/229) 活產率

MERiT – Key Messages MERiT is the largest randomized, prospective assessor-blind, multinational trial comparing MENOPUR and Gonal-F in IVF The number of top quality embryos per oocyte retrieved , as determined by local assessment, was higher in the MENOPUR group At the end of stimulation, the Gonal-F group exhibited significantly lower estrogen levels and higher progesterone levels MENOPUR is associated with a higher ongoing pregnancy rate compared with Gonal-F.

MERiT is the largest randomized, prospective assessor-blind, multinational trial comparing MENOPUR and Gonal-F in IVF

The number of top quality embryos per oocyte retrieved , as determined by local assessment, was higher in the MENOPUR group

At the end of stimulation, the Gonal-F group exhibited significantly lower estrogen levels and higher progesterone levels

MENOPUR is associated with a higher ongoing pregnancy rate compared with Gonal-F.

4. Administration of Menopur

Package of Menopur

Menopur 藥品使用方法衛教單張

注意事項： (1) 每一稀釋溶劑瓶最多可溶解 6 瓶 Menopur （白色粉末）藥物瓶。 (2)Menopur 需 避光 儲存，儲存溫度不可超過 25℃ ( 建議可放 於 2-8℃ 儲存 ) 。

注意事項：

(1) 每一稀釋溶劑瓶最多可溶解 6 瓶 Menopur （白色粉末）藥物瓶。

(2)Menopur 需 避光 儲存，儲存溫度不可超過 25℃ ( 建議可放 於 2-8℃ 儲存 ) 。

Thank you

Back-up slides

Immunologically active LH is lost to a greater extent than hCG during production of hMG-HP (Predominantly in the manufacture of fractions C and G) Purification Process of Menopur Step No . Hormone adsorption from urine Fraction O 1 Hormone elution from adsorbent Fraction A 2 Extraction with ethanol/ ammon.ac . Fraction B 3 Fraction 10C Discarded Anion exchange chromatography I Fraction C 4 Cation exchange chromatography Fraction F 5 Anion exchange chromatography II Fraction G 6 Fraction 10G Discarded Hydrophobic interaction chromatography Fraction J 7 Fraction J2 Fraction J4 Fraction J3 Pooling of eluates, precipitation, drying Fraction K M = HMG HP 8

Immunologically active LH is lost to a greater extent

than hCG during production of hMG-HP

(Predominantly in the manufacture of fractions C and G)

Final Procedure for Making MENOPUR, BRAVELLE and HP-HCG Fraction J Fraction J3 (FSH/LH activity  1:1) Fraction J2 (FSH only) Fraction J4 (hCG only) BRAVELLE MENOPUR Hp-hCG Used to correct ratio

子宮內膜變化 : 回音強度 (Echogenicity) 低回音性 Hyporechogenic S S S 高回音性 Hyperechogenic

子宮內膜變化 : 回音強度 (Echogenicity)

子宮內膜變化 厚度增加 回音度增強 排卵 黃體期 濾泡期 子宮內膜 Endometrium

子宮內膜變化

優質 子宮內膜 最理想的著床 (Implantation) 時間 雌激素 Estrogen 黃體素 Progesterone 2. 排卵 3. 黃體期 1. 濾泡期 最理想的 著床時間

最理想的著床 (Implantation) 時間

Fanchin et al., 2000 Echogenicity & Pregnancy rate

如何形成 優質 子宮內膜 ？ 雌激素 (Estrogen) 的 製造 Theca cell 外壁細胞 LH 有賴 FSH 及 LH 的協同作用 Granulosa cell 顆粒細胞 A A E E FSH 雄激素 Androgen 雌 激素 Estrogen Granulosa cell 顆粒細胞 Theca cell 外壁細胞

雌激素 (Estrogen) 的 製造

有賴 FSH 及 LH 的協同作用

如何形成 優質 子宮內膜 ？ 調節黃體素 ( Progesterone ) 的 製造 有賴 LH 的作用 LH 可加速 P 轉化成 A 外壁細胞 Theca cell Granulosa cell 顆粒細胞 Theca cell 外壁細胞 LH P A 雄激素 Androgen 黃體素 Progesterone

調節黃體素 ( Progesterone ) 的 製造

有賴 LH 的作用

Two Cell, Two Gonadotrophin Theory A + T A E2 Aromatase + FSH LH FSH Theca Internal Cell Granulosa Cell C T = Testosterone E2 = Estradiol LH receptor site FSH receptor site C = Cholesterol A = Androgen

Routes of Estrogen Conversion Acetate Cholesterol Pregnenolone 17-Hydroxypregnenolone Progesterone Dehydroepiandrosterone 17-Hydroxyprogesterone Androstenedione Estrone Testosterone Estradiol Aromatization Aromatization

Routes of Estrogen Conversion

Two Cell, Two Gonadotrophin Theory

Questions & Answers

1. MENOPUR 是什麼 ? 全新 , 天然 , 三合一促性腺激素 Brand new, natural, three-in-one gonadotropin

全新 , 天然 , 三合一促性腺激素

Brand new, natural, three-in-one gonadotropin

2. MENOPUR 是 MENOGON 或 REPRONEX 嗎 ? REPRONEX = MENOGON = 普通 HMG REPRONEX / MENOGON ≠ MENOPUR MENOPUR- 全新劑型 的促性腺激素 全新 , 天然 , 三合一促性腺激素

REPRONEX = MENOGON = 普通 HMG

REPRONEX / MENOGON ≠ MENOPUR

MENOPUR- 全新劑型 的促性腺激素

全新 , 天然 , 三合一促性腺激素

3. MENOPUR 含有什麼成份 ? MENOPUR 是源於天然的促性腺激素 , 含有 FSH , LH 和 hCG 的獨特組合

MENOPUR 是源於天然的促性腺激素 , 含有 FSH , LH 和 hCG 的獨特組合

4. MENOPUR 成份中的生物活性 (bioactivity) 是什麼 ? MENOPUR 的成份中包含 75 IU FSH activity 和 75 IU LH activity 但 95% 以上的 LH activity 是 來自 hCG -driven LH -activity

MENOPUR 的成份中包含 75 IU FSH activity 和 75 IU LH activity

但 95% 以上的 LH activity 是 來自 hCG -driven LH -activity

5. MENOPUR 的製造過程是什麼 ? 與一般 FSH 有何不同 ? 一般 FSH 的 製造過程是 採用 抗體層析純化技術 (Anti-bodies chrom a tographic purification ) MENOPUR 的 製造過程是 採用 創新專利 的 離子交換層析純化技術 (Ion exchange chromatographic purification)

一般 FSH 的 製造過程是 採用 抗體層析純化技術 (Anti-bodies chrom a tographic purification )

MENOPUR 的 製造過程是 採用 創新專利 的 離子交換層析純化技術 (Ion exchange chromatographic purification)

6. MENOPUR 的 hCG 是外加的嗎 ? 不是 , 是 內含 的 .

不是 , 是 內含 的 .

7. MENOPUR 的注射方式是什麼 ? 皮下注射 (SC injection) 或肌肉注射 (IM injection)

皮下注射 (SC injection) 或肌肉注射 (IM injection)

8. MENOPUR 有 FDA approved 嗎 ? 有

有

MENOPUR 的 原料 收集地在那裡 ? 阿根廷

MENOPUR 的 原料 收集地在那裡 ?

阿根廷

10. MENOPUR 具有批次間的一致性 (batch to batch consistency) 嗎 ? 有 根據一份在 2005 年的研究報告 , MENOPUR 能達到 90% 以上的 一致性 Wolfenson et al. (2005) 跟 rFSH 的 一致性 相當

有

根據一份在 2005 年的研究報告 , MENOPUR 能達到 90% 以上的 一致性

Wolfenson et al. (2005)

跟 rFSH 的 一致性 相當

11. MENOPUR 的溶劑成分是什麼 ? 一瓶溶劑是多少 cc? MENOPUR 的溶劑成分是 saline (0.9% sodium chloride) 一瓶溶劑是 1 cc (1mL)

MENOPUR 的溶劑成分是 saline (0.9% sodium chloride)

一瓶溶劑是 1 cc (1mL)

12. MENOPUR 的一瓶溶劑可溶解幾瓶 粉末 ? 一瓶溶劑可溶解 6 瓶粉末

一瓶溶劑可溶解 6 瓶粉末