reproductive health[生殖健康](ppt-91)

Reproductive Health Advisory Committee September 30, 2003 Pamela Williamson Joyce, RAC Vice President, Regulatory Affairs Received hCG Insufficient Follicular Development Ovarian Over-Response Cycles Cancelled Risk of OHSS 5/105/10 Cycle 1Cycle 1 225 IU225 IU Cycle 3Cycle 3 75 IU75 IU 3/33/3 Cycle 2Cycle 2 25 IU25 IU 1/51/5 7 6 5 4 3 2 1 10 9 8 5 4 37 6 5 4 3 44 Study 6253 Secondary Efficacy Parameters Cycle 1 Dose (IU LH)Dose (IU LH) Median Pre-Ovulatory EMedian Pre-Ovulatory E 2 2 Levels Levels (pg/ml)(pg/ml) n=9n=8 n=11n=10 Median Endometrial ThicknessMedian Endometrial Thickness (mm)(mm) n=9n=8n=11n=10 45 Study 6905 Study Design Controlled, parallel-designed, open-label, randomized, 3 cycle, dose-finding study in US July 1994 - July 1997 14 centers treated 40 subjects Dose Groups: 0, 25, 75, and 225 IU LH co-administered with 150 IU FSH daily Randomization Ratio - 1:1:1:1 in cycle 1 Fixed dose of LH and FSH within cycles 46 Study 6905 Study Design (contd) Major Differences to Study 6253 LH 1.2 IU/LLH 1.2 IU/L No Additional Benefit of LHNo Additional Benefit of LH 19922002 ConfirmatoryConfirmatory Phase III Study Phase III Study requested requested (LH 1.2 IU/LLH 1.2 IU/L No Additional Benefit of LHNo Additional Benefit of LH Rollover ExtensionRollover Extension Supportive EfficacySupportive Efficacy and Safety Dataand Safety Data (LH 1.2 IU/L)(LH 1.2 IU/L) 21415 ConfirmatoryConfirmatory Phase III Study Phase III Study requested requested (LH 1.2 IU/L;(LH 1.2 IU/L; placebo placebo vs vs 75 IU)75 IU) 21008 51 Efficacy Overview Confirmatory Phase III Trial Study 21008 52 Study 21008 Study Design Double-blind, randomized, placebo-controlled, multinational study in patients seeking pregnancy 37 centers initiated; 25 centers enrolled 39 patients Dose Groups: Placebo and 75 IU LH co-administered with 150 IU FSH daily Randomization Ratio - 1:2 Fixed dose of LH and FSH 53 Study 21008 Study Design (contd) Clinical Entry Criteria Amenorrhea Low gonadotropin levels LH 1.2 IU/L and FSH 5 IU/L (Profoundly LH- deficient) Negative progestin challenge test as indicator of chronic low estrogen status Treatment duration up to 14 days If follicular maturation was imminent, treatment could continue beyond 14 days Single cycle of treatment (roll-over possibility to extension Study 21415) 54 Study 21008 Study Population Diagnosis No. of Patients Primary Amenorrhea Kallmann Syndrome Pan-hypopituitarism Other endocrine defects Unspecified 7 1 2 10 Secondary Amenorrhea Other endocrine defects Multiple endocrine defects Pituitary tumor/surgery Unspecified 2 1 1 15 Total39 55 Study 21008 Percentage of Patients with Follicular Development 15.4%15.4% 65.4%65.4% 0%0% 10%10% 20%20% 30%30% 40%40% 50%50% 60%60% 70%70% PlaceboPlacebo75 IU LH75 IU LH 2/1317/26 p = 0.006p = 0.006 56 Study 21008 Percentage of Patients with Follicular Development 0%0% 10%10% 20%20% 30%30% 40%40% 50%50% 60%60% 70%70% PlaceboPlacebo75 IU LH75 IU LH 2/1317/26 7.7%7.7% 42.3%42.3% 1/1311/26 p = 0.006p = 0.006 p = 0.034p = 0.034 RiskRisk of OHSS of OHSS as a Failureas a Failure 15.4%15.4% 65.4%65.4% ITTITT 57 Study 21008 Comparison of Analyses Follicular Development Fishers Exact Fishers Exact p = 0.063p = 0.063Fishers Exact Fishers Exact p = 0.034p = 0.034 10/26 (38.5%)10/26 (38.5%)1/13 (7.7%)1/13 (7.7%)11/26 (42.3%)11/26 (42.3%)1/13 (7.7%)1/13 (7.7%) 75 IU75 IUPlaceboPlacebo75 IU75 IUPlaceboPlacebo FDAs AnalysisFDAs Analysis FDA Background Package, Section 2.2, Table 4FDA Background Package, Section 2.2, Table 4 Seronos AnalysisSeronos Analysis Serono Background Package, Table 6.1.1-2Serono Background Package, Table 6.1.1-2 Risk of OHSS as FailureRisk of OHSS as Failure 16/26 (61.5%)16/26 (61.5%)2/13 (15.4%)2/13 (15.4%)17/26 (65.4%)17/26 (65.4%)2/13 (15.4%)2/13 (15.4%) Fishers Exact Fishers Exact p = 0.008p = 0.008Fishers Exact Fishers Exact p = 0.006p = 0.006 75 IU75 IUPlaceboPlacebo75 IU75 IUPlaceboPlacebo FDAs AnalysisFDAs Analysis FDA Background Package, Section 2.2, Table 4FDA Background Package, Section 2.2, Table 4 Seronos AnalysisSeronos Analysis Serono Background Package, Table 6.1.1-1Serono Background Package, Table 6.1.1-1 Primary AnalysisPrimary Analysis 58 Studies 21008 and 21415 Protocol Definition of Success “The primary efficacy endpoint will be follicular development as defined by the following three parameters, all of which must be true: At least one follicle with a mean diameter 17 mm and Preovulatory E2 serum level 109 pg/mL (400 pmol/L) and Mid-luteal phase P4 level 7.9 ng/mL (25 nmol/L) Should any patient be cancelled for Risk of OHSS, that patient will be counted as achieving follicular development. Should any patient achieve pregnancy, that patient will be counted as having achieved follicular development.” 59 Study 21008 Patient 251-0001 Lead Follicle20 mm( 17 mm) E2106 pg/mL( 109 pg/mL) P413.2 ng/mL( 7.9 ng/mL) March 7, 2000 Day of hCG April 4, 2000Serum hCG 102 mIU/mL ( 10 mIU/mL) April 6, 2000Serum hCG 51 mIU/mL 60 Efficacy Overview Extension Study 21415 61 Study Eligibility for 21415 Confirmatory Study 21008 Treatment Extension Study 21415 1.1. Open Label Treatment:Open Label Treatment: 75 IU LH and individualized 75 IU LH and individualized dose of FSH (75-225 IU) dose of FSH (75-225 IU) based on patients previous based on patients previous responseresponse 2.2. Consistent Primary EndpointConsistent Primary Endpoint If no SAE or OHSS If no SAE or OHSS and not pregnant and not pregnant 1 Cycle Treatment1 Cycle Treatment Up to 3 Additional CyclesUp to 3 Additional Cycles of Treatmentof Treatment 62 Cycle 3 n=8 n=31 Cycle 1 n=31 Cycle 2 n=15 Study 21415 Patient Disposition 31 of 39 patients in Study 21008 enrolled 31 of 39 patients in Study 21008 enrolled and treated with 75 IU r-hLH in Study 21415and treated with 75 IU r-hLH in Study 21415 11 Treated in 21008 with Placebo11 Treated in 21008 with Placebo 20 Treated in 21008 with 75 IU r-hLH20 Treated in 21008 with 75 IU r-hLH 63 Study 21415 Cumulative Follicular Development with 75 IU Cycle Cancellation for Cycle Cancellation for RiskRisk of OHSS of OHSS is mitigated with individualization of FSH doseis mitigated with individualization of FSH dose 21/3126/3127/31 With With RiskRisk of OHSS counted of OHSS counted as as SuccessSuccess With With RiskRisk of OHSS counted of OHSS counted as as FailureFailure 16/3126/3127/31 64 Studies 21008 and 21415 Impact of Cycle Cancellation for Risk of OHSS on Response in Subsequent Cycles Cycle cancellation due to the Risk of OHSS is a normal precaution in clinical practice Ovarian over-response is a treatment effect and provides guidance for next cycle of treatment 4 of the 11 patients whose cycles were cancelled due to Risk of OHSS in 1st cycle of Study 21008 or 21415 achieved pregnancy in Study 21415 with adjustment of FSH dose in subsequent cycle 65 Study 21415 Sub Group: LH Nave Patients (n=11) Follicular Development and Pregnancy 1/117/114/110/110/11 66 Study 21415 Pregnancies Cycle 3 n=8 n=31 Received hCG = 27 Cycle 1 n=31 Cycle 2 n=15 Cumulative Total Pregnancy Rate in Patients Cumulative Total Pregnancy Rate in Patients Receiving hCG = 20/27 (74.1%)Receiving hCG = 20/27 (74.1%) 11 Pregnancies 9 Pregnancies 0 Pregnancies 67 Study 21415 Clinical Pregnancies Cycle 3 n=8 n=31 Received hCG = 27 Cycle 1 n=31 Cycle 2 n=15 Cumulative Clinical Pregnancy Rate in Patients Cumulative Clinical Pregnancy Rate in Patients Receiving hCG = 16/27 (59.3%)Receiving hCG = 16/27 (59.3%) 11 Pregnancies 5 Pregnancies 0 Pregnancies 68 Summary of Pregnancy Results and Pregnancy Outcomes 69 Studies 6253, 21008 and 21415 Pregnancy Rates in Profoundly LH Deficient Women (LH 1.2 IU/L) Treatment GroupPlacebo/0 IU25 IU LH75 IU LH225 IU LH Patients Seeking Pregnancy 229488 Cycles of Treatment in Patients Seeking Pregnancy 229918 Total Pregnancies n (% patients) % cycles 2 (9.1%)0 24 (50%) 26.4% 1 (12.5%) Clinical Pregnancies n (% patients) % cycles 1 (4.5%)0 19 (39.6%) 20.9% 1 (12.5%) 70 All Studies Pregnancy Outcome for Patients Seeking Pregnancy Treatment GroupPlacebo/0 IU25 IU LH75 IU LH150 IU LH225 IU LH Patients Seeking Pregnancy 41191111330 Cycles of Treatment 41191961430 Total Pregnancies 725126 Clinical Pregnancies 514414 Clinical Pregnancies Leading to Live Births 413513 Single Twins Triplets 2 2 0 0 1 0 22 12 1 0 1 0 2 1 0 Miscarriage 20601 Lost to follow-up 00300 Other 10200 Stillbirth 00100 71 Efficacy Conclusions 72 Efficacy Conclusions Study 6253 provides rationale for selection of 75 IU r-hLH as the appropriate dose for HH patients with profound LH deficiency (LH 1.2 IU/L) No benefit of 25 IU dose of r-hLH No additional benefit of 225 IU dose of r-hLH Study 21008, the randomized, double-blind, placebo-controlled study, confirmed the efficacy of 75 IU r-hLH dose in the profoundly LH deficient (LH 1.2 IU/L) patient population 73 Efficacy Conclusions (contd) Study 21415 supports the efficacy of 75 IU as used in standard clinical practice with individualized dosing Cumulative follicular development rate 87.1% Cumulative pregnancy rate 74.1% Overall, a 50% (24/48) pregnancy rate in profoundly LH-deficient women* (LH 1.2 IU/L) on 75 IU dose * Studies 6253, 21008, and 21415* Studies 6253, 21008, and 21415 74 Overview of Safety 75 Safety Conclusions Largest safety database in Female HH Patients (170 patients, 152 received r-hLH in 283 cycles) No increase in adverse events when r-hLH is co-administered with r-hFSH, compared to r-hFSH alone Similar rates of OHSS across all dose groups, including r-hFSH alone Safety profile of r-hLH comparable to currently marketed gonadotropins 76 Overall Conclusions Luveris Clinical Development Program Among women with HH, a cut-off value of 1.2 IU/L differentiates between LH-dependence and LH-independence Follicular development is an appropriate endpoint in this population and correlates with pregnancy Canceling a cycle is prudent clinical practice in an over-responding patient with follicular development Women with profound LH-deficiency clearly benefit from treatment with Luveris 75 IU The safety profile of Luveris is similar to other gonadotropins and is not different from treatment with FSH alone 77 Clinical Perspective and Risk/Benefit Assessment Nanette F. Santoro, MD Professor and Director, Division of Reproductive Endocrinology Department of Obstetrics and Gynecology and Womens Health Albert Einstein College of Medicine 78 Hypogonadotropic Hypogonadism (HH) Women and Infertility Absence of pubertal development Single endocrine factor Potential to be highly fertile when ovarian responsiveness is restored LH (in addition to FSH) is needed for optimal follicle growth Induction of follicular development as a prelude to fertility is the therapeutic goal 79 Follicular Maturation FSH Induces early growth Controls follicle number LH Provides estrogen precursors Needed for latter stages of growth 80 r-hFSH in Woman with HH: Follicle Growth Without Estradiol Follicular sizeFollicular size (mm)(mm) r-hFSHr-hFSH (IU/day)(IU/day) 7575 150150 0 0 hCGhCG (10,000 IU)(10,000 IU) 2020 1515 5 5 1010 0 0 8 8 6 6 2 2 4 4 0 0 FSH (IU/L)FSH (IU/L) LH (IU/L)LH (IU/L) Estradiol (pmol/L)Estradiol (pmol/L) 81 * 81 Risk of OHSS vs OHSS 3 Developing Follicles3 Developing Follicles OHSS: Massive Ovarian OHSS: Massive Ovarian Enlargement and Enlargement and Multiple CystsMultiple Cysts 82 Follicular Development in HH Give back whats missing GnRH highly effective if intact pituitary function, but not available Alternative strategy: exogenous gonadotropins (u-hMG), but combined fixed ratio and IM administration is a limitation to treatment Optimal strategy: stand-alone recombinant human LH and FSH allows titration and individualization 83 Recombinant LH Permissive and obligatory for follicle