Luveris FDA Presentation

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Luveris FDA Presentation

  1. 1. Reproductive Health Advisory Committee September 30, 2003 Pamela Williamson Joyce, RAC Vice President, Regulatory Affairs & Quality Assurance – US Serono, Inc. NDA # 21-322
  2. 2. Proposed Indication – Luveris ® Luveris ® (lutropin alfa for injection) administered with follitropin alfa for injection, is indicated for stimulation of follicular development in infertile hypogonadotropic hypogonadal women with profound LH deficiency (LH < 1.2 IU/L)* * The indication presented in the NDA was amended on August 21, 2003 to be consistent with the indication as currently approved for Luveris ® in the European Union and other countries outside of the United States
  3. 3. Agenda Nanette F. Santoro, M.D. Professor and Director, Division of Reproductive Endocrinology Department of Obstetrics and Gynecology and Women’s Health Albert Einstein College of Medicine Clinical Perspective and Risk/Benefit Assessment Pamela Williamson Joyce, RAC Serono, Inc. Summary and Conclusions Paul Lammers, M.D. Chief Medical Officer Serono, Inc. Luveris ® Clinical Development Program Jerome Strauss, M.D., Ph.D. Luigi Mastroianni Jr. Professor Director, Center for Research on Reproduction and Women’s Health University of Pennsylvania Need for and Role of LH: HH Women with Profound Gonadotropin Deficiency Pamela Williamson Joyce, RAC Vice President, Regulatory Affairs & Quality Assurance – US Serono, Inc. Introduction and Regulatory History
  4. 4. Luveris ® (lutropin alfa for injection) <ul><li>Luteinizing hormone produced by recombinant DNA technology </li></ul><ul><li>Common names </li></ul><ul><ul><li>Recombinant human luteinizing hormone </li></ul></ul><ul><ul><li>r-hLH </li></ul></ul><ul><li>Lyophilized powder in 75 IU vials </li></ul><ul><li>Self-administered by subcutaneous injection </li></ul>
  5. 5. Currently Approved in 46 Countries Portugal Holland Austria United Kingdom Mauritius Estonia Germany Venezuela Norway France Uruguay Mexico Finland Trinidad & Tobaggo Luxemburg Dominican Republic Switzerland Lithuania Denmark Sweden Latvia Czech Republic Sri Lanka Italy Costa Rica Spain Israel Colombia Slovenia Ireland Chile Slovak Republic Iceland Bulgaria Singapore Hungary Brazil Romania Hong Kong Belgium Poland Guatemala Australia Peru Greece Argentina
  6. 6. Orphan Drug Designation for Luveris ® * OOPD # 94-802 Hypogonadotropic Hypogonadal Women 2,800-5,600 (1/50,000-1/25,000)* Prevalence “ For use in association with recombinant human follicle stimulating hormone for the treatment of women with chronic anovulation due to hypogonadotropic hypogonadism” Provides incentive for the development of drugs to treat rare diseases and conditions Orphan Drug Regulation Prevalence < 200,000 patients with the disease in the US Rare Disease or Condition
  7. 7. Regulatory History – Luveris ® Clinical Development Program Pre-NDA meeting with FDA Division of Reproductive and Urologic Drug Products December 2000 NDA submitted to FDA April 2001 Studies completed – 2 different populations – insufficient for NDA filing Confirmatory Phase III trial (Study 21008) required for approval March 1999 Pre-IND Meeting - clinical program of r-hLH for follicular development 2 Phase II/III Studies (6253, 6905) May 1992
  8. 8. Regulatory History – Luveris ® (cont’d) Clinical Development Program FDA will bring Luveris ® before Advisory Committee January 2003 Type A meeting – cycle cancellation due to Risk of OHSS April 2002 <ul><li>Not Approvable Letter </li></ul><ul><li>Insufficient evidence to support efficacy of the 75 IU/day dose </li></ul><ul><li>Conduct another Phase III study </li></ul><ul><ul><li>Efficacy vs. Placebo </li></ul></ul><ul><ul><li>Ovulation induction </li></ul></ul><ul><ul><li>Dose ranging </li></ul></ul><ul><ul><li>Placebo, 75 IU and lower dose (50 or 25 IU) </li></ul></ul>March 2002
  9. 9. Regulatory History – Luveris ® (cont’d) Clinical Development Program NDA amended to revise indication August 2003 NDA amended to include results from extension study (21415) for confirmatory phase III trial April 2003
  10. 10. Topics for Discussion <ul><li>Is there a need for recombinant luteinizing hormone? </li></ul><ul><li>Has the appropriate patient population been defined? </li></ul><ul><li>Has a safe and effective dose been identified? </li></ul><ul><ul><li>75 IU/day </li></ul></ul><ul><li>Is the composite primary endpoint of follicular development an appropriate endpoint to assess efficacy in this patient population? </li></ul>
  11. 11. Topics for Discussion (cont’d) <ul><li>Is the definition of treatment success appropriate? </li></ul><ul><ul><li>Primary efficacy endpoint </li></ul></ul><ul><ul><ul><li>Follicular development </li></ul></ul></ul><ul><ul><li>Cancellation for the Risk of OHSS </li></ul></ul><ul><ul><li>Pregnancy </li></ul></ul><ul><ul><ul><li>Serum  -hCG pregnancy test and/or ultrasound </li></ul></ul></ul><ul><li>Do the data support the safety and efficacy of Luveris ® in the proposed indication? </li></ul><ul><li>Should another phase III double-blind placebo-controlled clinical trial be required for approval of Luveris ® in patients with this rare condition? </li></ul>
  12. 12. External Consultant Experts <ul><li>Sarah L. Berga, MD </li></ul><ul><ul><li>James Robert McCord Professor and Chair Department of Gynecology and Obstetrics Emory University School of Medicine </li></ul></ul><ul><li>Michael Diamond, MD </li></ul><ul><ul><li>Kamram S. Moghissi Professor and Associate Chair of Obstetrics and Gynecology, Director, Division of Reproductive Endocrinology & Infertility Wayne State University (Detroit, MI) </li></ul></ul><ul><li>Gary Koch, PhD </li></ul><ul><ul><li>Statistical Consultant Chapel Hill, NC </li></ul></ul>
  13. 13. External Consultant Experts (cont’d) <ul><li>Bert Spilker, MD, PhD </li></ul><ul><ul><li>Co-founder and former President Orphan Medical </li></ul></ul><ul><ul><li>Adjunct Professor of Medicine; Clinical Professor of Pharmacy University of North Carolina (Chapel Hill, NC) </li></ul></ul><ul><li>Nanette F. Santoro, MD </li></ul><ul><ul><li>Professor and Director, Division of Reproductive Endocrinology </li></ul></ul><ul><ul><li>Department of Obstetrics and Gynecology and Women’s Health Albert Einstein College of Medicine (NY) </li></ul></ul><ul><li>Jerome Strauss, MD, PhD </li></ul><ul><ul><li>Luigi Mastroianni Jr Professor </li></ul></ul><ul><ul><li>Director, Center for Research on Reproduction and Women’s Health University of Pennsylvania </li></ul></ul><ul><ul><li>Associate Chairman, Department of Obstetrics and Gynecology </li></ul></ul>
  14. 14. Need for and Role of LH in HH Women with Profound Gonadotropin Deficiency Jerome F. Strauss III, MD, PhD Luigi Mastroianni Jr Professor Director, Center for Research on Reproduction & Women’s Health University of Pennsylvania Associate Chairman, Department of Obstetrics and Gynecology
  15. 15. Outline <ul><li>Heterogeneity of pathophysiology and phenotype in Hypogonadotropic Hypogonadism (HH) </li></ul><ul><li>Consequences of profound LH deficiency </li></ul><ul><li>Current therapeutic options for HH </li></ul><ul><li>Unmet medical need </li></ul>
  16. 16. HH Can Be Caused by Hypothalamic Disorders, Pituitary Disease or Both Hypothalamus Pituitary Ovary CNS Influence Steroidal and Nonsteroidal Feedback GnRH LH FSH
  17. 17. HH: A Rare, Heterogeneous Condition <ul><li>Pathophysiology </li></ul><ul><li>Congenital </li></ul><ul><li>Acquired </li></ul><ul><li>Variable deficiency </li></ul><ul><ul><li>Pan-hypopituitarism </li></ul></ul><ul><ul><li>Isolated gonadotropin deficiency </li></ul></ul><ul><ul><li>Moderate impairment </li></ul></ul>
  18. 18. Diagnosis of Profound LH Deficiency in HH <ul><li>Serum LH levels < 1.2 IU/L </li></ul><ul><ul><li>Shoham Z et al. Fertil Steril 1991; 56:1048-1053 </li></ul></ul><ul><li>Endocrine or functional evidence of estradiol deficiency </li></ul><ul><ul><li>Estradiol level <30 pg/ml </li></ul></ul><ul><ul><li>Failed progestin challenge test </li></ul></ul>
  19. 19. Outline <ul><li>Heterogeneity of pathophysiology and phenotype in Hypogonadotropic Hypogonadism (HH) </li></ul><ul><li>Consequences of profound LH deficiency </li></ul><ul><li>Current therapeutic options for HH </li></ul><ul><li>Unmet medical need </li></ul>
  20. 20. Role of LH in Ovarian Function <ul><li>Follicular steroidogenesis </li></ul><ul><ul><li>Stimulation of androgen synthesis by theca cells </li></ul></ul><ul><li>Follicular maturation </li></ul><ul><ul><li>Can support terminal stages of follicular maturation </li></ul></ul><ul><li>Ovulation </li></ul><ul><ul><li>Resumption of meiosis </li></ul></ul><ul><ul><li>Ovulation </li></ul></ul><ul><ul><li>Luteinization </li></ul></ul><ul><li>Maintenance of luteal function </li></ul>
  21. 21. LH and FSH Action on the Follicle Theca externa cells Theca interna cells Capillary network Basement membrane Cumulus Oophorus cells Oocyte Zona pellucida Granulosa cells Follicular antrum LH receptors on theca cells FSH receptors on granulosa cells FSH LH E 2 A
  22. 22. Ovarian Defects in LH Receptor KO Mice Zhang et al. Mol Endocrinol . 15:172-183, 2001.
  23. 23. HH Treated with r-hFSH Alone Shoham Z et al. Fertil Steril 1993; 59:738 0 5 10 15 0 5 10 15 20 Days Serum FSH 50 100 Follicle Estradiol Estradiol (pg/ml) Follicle Size (mm) and FSH (IU/L) Endometrial Thickness (mm) r-hFSH 0 9
  24. 24. HH Treated with r-hFSH and r-hLH Estradiol (pg/ml) Serono data Study 6253 Follicle Size (mm) and FSH (IU/L) r-hFSH r-hLH 0 5 10 15 0 5 10 15 20 Days 50 100 20 Serum FSH Follicle Estradiol 150 200 250 300 350 400 0 0 9 Endometrial Thickness (mm)
  25. 25. The LH Therapeutic Window Concept Balasch J, F ábreques F. Curr Opin Obstet Gynecol 2002, 14:265-274 <ul><li>Follicular growth impaired </li></ul><ul><li>Inadequate androgen (and estrogen) synthesis </li></ul><ul><li>No full oocyte maturation </li></ul>LH threshold Normal follicular growth and development Normal androgen and estrogen biosynthesis Normal oocyte maturation <ul><li>Suppression of granulosa cell proliferation </li></ul><ul><li>Follicular atresia (nondominant follicles) </li></ul><ul><li>Premature luteinization (preovulatory follicle) </li></ul><ul><li>Oocyte development compromised </li></ul>LH ceiling
  26. 26. Outline <ul><li>Heterogeneity of pathophysiology and phenotype in Hypogonadotropic Hypogonadism (HH) </li></ul><ul><li>Consequences of profound LH deficiency </li></ul><ul><li>Current therapeutic options for HH </li></ul><ul><li>Unmet medical need </li></ul>
  27. 27. Current Therapeutic Options for HH <ul><li>Gonadotropin Releasing Hormone (GnRH) </li></ul><ul><li>Pro </li></ul><ul><ul><li>Effective in women with hypothalamic disease and intact pituitary </li></ul></ul><ul><ul><li>Monofollicular ovulation </li></ul></ul><ul><li>Con </li></ul><ul><ul><li>Approved but discontinued </li></ul></ul><ul><ul><li>Requires long-term pulsatile infusion </li></ul></ul>
  28. 28. Current Therapeutic Options for HH <ul><li>Human Menopausal Gonadotropins (hMG) </li></ul><ul><li>Pro </li></ul><ul><ul><li>Reported to be effective in mostly small, uncontrolled series </li></ul></ul><ul><ul><li>Can be used in women with hypothalamic and/or pituitary disease </li></ul></ul><ul><li>Con </li></ul><ul><ul><li>Fixed ratio of FSH and LH </li></ul></ul><ul><ul><li>Ovarian Hyperstimulation Syndrome (OHSS) </li></ul></ul><ul><ul><li>Multiple gestation </li></ul></ul>
  29. 29. Outline <ul><li>Heterogeneity of pathophysiology and phenotype in Hypogonadotropic Hypogonadism (HH) </li></ul><ul><li>Consequences of profound LH deficiency </li></ul><ul><li>Current therapeutic options for HH </li></ul><ul><li>Unmet medical need </li></ul>
  30. 30. Unmet Medical Need <ul><li>No FDA approved LH-only treatment for profoundly LH deficient patients </li></ul><ul><li>Individualization/titration </li></ul><ul><ul><li>No options available for individualization of treatment </li></ul></ul><ul><li>Recombinant Product </li></ul><ul><ul><li>Purity </li></ul></ul><ul><ul><li>Consistency </li></ul></ul><ul><ul><li>S.C. administration </li></ul></ul>
  31. 31. Conclusions <ul><li>LH is required for follicular competency </li></ul><ul><li>HH is a very rare, heterogeneous disorder </li></ul><ul><li>HH women profoundly deficient in LH require exogenous LH for normal follicular function </li></ul><ul><li>Optimal therapy of HH is based on individualized treatment </li></ul>
  32. 32. Luveris ® Clinical Development Program Paul Lammers, MD Chief Medical Officer Serono, Inc.
  33. 33. Presentation Outline <ul><li>Luveris ® (r-hLH) Clinical Development Program </li></ul><ul><ul><li>Study Design Considerations </li></ul></ul><ul><ul><li>Study Endpoints & Definition of Treatment Effect </li></ul></ul><ul><li>Dose Finding Studies </li></ul><ul><li>Efficacy Overview </li></ul><ul><ul><li>Confirmatory Phase III Study 21008 </li></ul></ul><ul><ul><li>Extension Study 21415 </li></ul></ul><ul><ul><li>Pregnancies & Pregnancy Outcomes </li></ul></ul><ul><li>Safety Overview </li></ul><ul><li>Overall Conclusions </li></ul>
  34. 34. Clinical Development Program of Luveris ® * Fixed Dose of 150 IU r-hFSH 75, 150, 225 15 Profoundly LH / FSH deficient Dose Response, Uncontrolled 7798* 75 31 Profoundly LH / FSH deficient Extension to 21008 21415 Placebo, 75 39 Profoundly LH / FSH deficient Confirmatory, Double-Blind 21008* 75, 150, 225 38 Hypo / hypo Sequential Dosing, Uncontrolled 8297* 0, 25, 75, 225 40 Hypo / hypo Dose Finding 6905* 0, 25, 75, 225 38 Profoundly LH / FSH deficient Dose Finding 6253* r-hLH Doses (IU) No. of Patients Population Description Study
  35. 35. Design Considerations Dose Finding Studies and Confirmatory Study 21008 <ul><li>Study design considerations </li></ul><ul><ul><li>Identify a clear dose response </li></ul></ul><ul><ul><li>Focus on effect of LH treatment only </li></ul></ul><ul><ul><li>Avoid potential confounder: change in FSH dose </li></ul></ul><ul><ul><li>Fix the dose of LH and FSH in each cycle </li></ul></ul><ul><li>Clinical considerations </li></ul><ul><ul><li>Absence of pre-existing data in this population </li></ul></ul><ul><ul><li>Provide adequate starting dose of FSH (150 IU) </li></ul></ul><ul><ul><li>Conservative criteria for discontinuing treatment for ovarian over-response ( Risk of OHSS) </li></ul></ul>
  36. 36. Primary Composite Efficacy Endpoint: Capture Various Actions of LH <ul><li>Synergistic Action of LH with FSH on Follicular Growth </li></ul><ul><ul><li>Follicle size  17 mm </li></ul></ul><ul><ul><ul><li>Normal pre-ovulatory size </li></ul></ul></ul><ul><li>Necessary Role of LH in Enabling Follicular Function </li></ul><ul><ul><li>Serum E 2  109 pg/ml (400 pmol/L) </li></ul></ul><ul><ul><ul><li>Lower limit of normal, and adequate for endometrial response </li></ul></ul></ul><ul><li>Contribution of LH to Corpus Luteum Competence, after hCG Administration </li></ul><ul><ul><li>Mid-luteal P 4  7.9 ng/ml (25 nmol/L) </li></ul></ul><ul><ul><ul><li>Above threshold for normal ovulating women (  6.0 ng/mL) </li></ul></ul></ul>
  37. 37. Definition of Treatment Success <ul><li>Composite Endpoint – Follicular Development </li></ul><ul><li>1. At least one follicle  17 mm in diameter </li></ul><ul><li>2. Pre-ovulatory Serum Estradiol  109 pg/ml (400 pmol/L) </li></ul><ul><li>3. Mid-luteal Phase Serum P 4  7.9 ng/ml (25 nmol/L) </li></ul><ul><li>OR </li></ul><ul><li>Pregnancy Positive  -hCG (>10 mIU/mL) or confirmatory Ultrasound </li></ul><ul><li>OR </li></ul><ul><li>Cycle Cancellation for Risk of OHSS </li></ul><ul><ul><ul><li>Ovarian Response: 3 follicles  15 mm and/or E 2 level >1100 pg/ml </li></ul></ul></ul>
  38. 38. Key Secondary Efficacy Endpoints <ul><li>Estradiol (E 2 ) level </li></ul><ul><li>Endometrial thickness (mm) </li></ul><ul><ul><li>Receptive uterine ‘milieu’ </li></ul></ul><ul><li>Pregnancy Rate </li></ul>
  39. 39. Dose Finding Studies Study 6253 and Study 6905
  40. 40. Study 6253 Study Design <ul><li>Controlled, parallel-designed, open-label, randomized, 3 cycle, dose-finding </li></ul><ul><ul><li>Multinational study: September 1993 - April 1995 </li></ul></ul><ul><ul><li>38 subjects enrolled in 10 centers in 4 countries </li></ul></ul><ul><li>Standard dose-finding approach </li></ul><ul><ul><li>r-hFSH: 150 IU per day </li></ul></ul><ul><ul><li>r-hLH: 0, 25, 75, and 225 IU per day (1:1:1:1 in Cycle 1) </li></ul></ul><ul><ul><li>Protocol pre-specified an Armitage trend test to detect relationship between the LH dose and follicular development in Cycle 1 </li></ul></ul><ul><li>Adequately powered at 85% </li></ul>
  41. 41. Study 6253 Study Design (cont’d) <ul><li>Clinical Entry Criteria </li></ul><ul><ul><li>Amenorrhea </li></ul></ul><ul><ul><li>Low gonadotropin levels </li></ul></ul><ul><ul><ul><li>LH < 1.2 IU/L and FSH < 5 IU/L (Profoundly LH-deficient) </li></ul></ul></ul><ul><ul><li>Negative progestin challenge test as indicator of chronic low estrogen status </li></ul></ul><ul><li>Treatment duration up to 14 days </li></ul><ul><ul><li>If follicular response was ongoing (E 2 rise and follicle > 10 mm), treatment could continue beyond 14 days </li></ul></ul><ul><li>Primary and secondary endpoints to be analyzed in cycle 1 </li></ul><ul><li>Pregnancy rates to be evaluated across all 3 cycles </li></ul>
  42. 42. Study 6253 Study Population 8 2 <ul><li>Secondary Amenorrhea </li></ul><ul><li>Functional or idiopathic isolated gonadotropin deficiency </li></ul><ul><li>Trauma- or tumor-related multiple pituitary deficiencies </li></ul>7 14 1 6 <ul><li>Primary Amenorrhea </li></ul><ul><li>Kallmann Syndrome </li></ul><ul><li>Idiopathic, isolated HH </li></ul><ul><li>Trauma- or tumor-related isolated gonadotropin deficiency </li></ul><ul><li>Multiple pituitary deficiencies </li></ul>38 Total No. of Patients Diagnosis
  43. 43. Study 6253 Percentage of Patients with Follicular Development – Cycle 1 1/9 2/8 7/11 7/10 p = 0.467 p = 0.020 p = 0.012 p-values vs 0 IU LH Trend Test* p = 0.004 * Statistically significant and robust
  44. 44. Study 6253 Results for Patients Randomized to 225 IU in Cycle 1 Adequate Follicular Development; Received hCG Insufficient Follicular Development Ovarian Over-Response Cycles Cancelled Risk of OHSS 5/10 Cycle 1 225 IU Cycle 3 75 IU 3/3 Cycle 2 25 IU 1/5 7 7 6 5 4 3 2 1 10 9 8 5 4 3 6 5 4 3
  45. 45. Study 6253 Secondary Efficacy Parameters – Cycle 1 Dose (IU LH) Median Pre-Ovulatory E 2 Levels (pg/ml) n=9 n=8 n=11 n=10 Median Endometrial Thickness (mm) n=9 n=8 n=11 n=10
  46. 46. Study 6905 Study Design <ul><li>Controlled, parallel-designed, open-label, randomized, 3 cycle, dose-finding study in US </li></ul><ul><ul><li>July 1994 - July 1997 </li></ul></ul><ul><ul><li>14 centers treated 40 subjects </li></ul></ul><ul><li>Dose Groups: 0, 25, 75, and 225 IU LH co-administered with 150 IU FSH daily </li></ul><ul><ul><li>Randomization Ratio - 1:1:1:1 in cycle 1 </li></ul></ul><ul><li>Fixed dose of LH and FSH within cycles </li></ul>
  47. 47. Study 6905 Study Design (cont’d) <ul><li>Major Differences to Study 6253 </li></ul><ul><ul><li>LH < 13 IU/L and FSH < 11 IU/L* </li></ul></ul><ul><ul><ul><li>Broader HH population </li></ul></ul></ul><ul><ul><li>No progestin challenge test; E 2 < 60 pg/mL </li></ul></ul><ul><ul><li>Treatment duration up to 21 days </li></ul></ul><ul><ul><ul><li>If follicular maturation was imminent, treatment could continue beyond 21 days </li></ul></ul></ul>* <50 th percentile normal
  48. 48. Study 6905 Percentage of Patients with Follicular Development 7/11 9/9 8/11 6/9 Trend Test p = 0.774 Conclusion: the benefit of LH treatment was not demonstrated in the broader HH patient population
  49. 49. Luveris ® Clinical Development Program in Support of US Registration 2 Phase II / III Dose Response Studies 6253 LH < 1.2 IU/L Benefit of LH 6905 Broader HH population LH > 1.2 IU/L No Additional Benefit of LH 1992 2002 Confirmatory Phase III Study requested (LH < 1.2 IU/L; placebo vs 75 IU) 21008
  50. 50. Lowest Effective Dose <ul><li>Reasonable and sufficient range of doses studied (0, 25, 75, and 225 IU) </li></ul><ul><li>25 IU dose </li></ul><ul><ul><li>Not clinically/statistically different from 0 IU </li></ul></ul><ul><ul><li>75% non-response </li></ul></ul><ul><li>75 IU dose </li></ul><ul><ul><li>Clinically/statistically different from 0 IU in primary endpoint (more than a five-fold increase in patient response) </li></ul></ul><ul><ul><li>Clinically different from 0 IU in secondary endpoints (E 2 levels, and endometrial response) </li></ul></ul><ul><li>225 IU dose </li></ul><ul><ul><li>No additional benefit in efficacy compared to 75 IU </li></ul></ul>75 IU is the minimum effective dose providing maximum therapeutic benefit
  51. 51. Luveris ® Clinical Development Program in Support of US Registration 2 Phase II / III Dose Response Studies 6253 LH < 1.2 IU/L Benefit of LH 6905 Broader HH population LH > 1.2 IU/L No Additional Benefit of LH Rollover Extension Supportive Efficacy and Safety Data (LH <1.2 IU/L) 21415 Confirmatory Phase III Study requested (LH < 1.2 IU/L; placebo vs 75 IU) 21008 1992 2002
  52. 52. Efficacy Overview Confirmatory Phase III Trial Study 21008
  53. 53. Study 21008 Study Design <ul><li>Double-blind, randomized, placebo-controlled, multinational study in patients seeking pregnancy </li></ul><ul><ul><li>37 centers initiated; 25 centers enrolled 39 patients </li></ul></ul><ul><li>Dose Groups: Placebo and 75 IU LH co-administered with 150 IU FSH daily </li></ul><ul><ul><li>Randomization Ratio - 1:2 </li></ul></ul><ul><li>Fixed dose of LH and FSH </li></ul>
  54. 54. Study 21008 Study Design (cont’d) <ul><li>Clinical Entry Criteria </li></ul><ul><ul><li>Amenorrhea </li></ul></ul><ul><ul><li>Low gonadotropin levels </li></ul></ul><ul><ul><ul><li>LH < 1.2 IU/L and FSH < 5 IU/L (Profoundly LH-deficient) </li></ul></ul></ul><ul><ul><li>Negative progestin challenge test as indicator of chronic low estrogen status </li></ul></ul><ul><li>Treatment duration up to 14 days </li></ul><ul><ul><li>If follicular maturation was imminent, treatment could continue beyond 14 days </li></ul></ul><ul><li>Single cycle of treatment (roll-over possibility to extension Study 21415) </li></ul>
  55. 55. Study 21008 Study Population 2 1 1 15 <ul><li>Secondary Amenorrhea </li></ul><ul><li>Other endocrine defects </li></ul><ul><li>Multiple endocrine defects </li></ul><ul><li>Pituitary tumor/surgery </li></ul><ul><li>Unspecified </li></ul>7 1 2 10 <ul><li>Primary Amenorrhea </li></ul><ul><li>Kallmann Syndrome </li></ul><ul><li>Pan-hypopituitarism </li></ul><ul><li>Other endocrine defects </li></ul><ul><li>Unspecified </li></ul>39 Total No. of Patients Diagnosis
  56. 56. Study 21008 Percentage of Patients with Follicular Development 15.4% 65.4% 0% 10% 20% 30% 40% 50% 60% 70% Placebo 75 IU LH 2/13 17/26 p = 0.006
  57. 57. Study 21008 Percentage of Patients with Follicular Development 0% 10% 20% 30% 40% 50% 60% 70% Placebo 75 IU LH 2/13 17/26 p = 0.006 p = 0.034 Risk of OHSS as a Failure 15.4% 65.4% ITT 7.7% 42.3% 1/13 11/26
  58. 58. Study 21008 Comparison of Analyses – Follicular Development Fisher’s Exact p = 0.063 Fisher’s Exact p = 0.034 10/26 (38.5%) 1/13 (7.7%) 11/26 (42.3%) 1/13 (7.7%) 75 IU Placebo 75 IU Placebo FDA’s Analysis FDA Background Package, Section 2.2, Table 4 Serono’s Analysis Serono Background Package, Table 6.1.1-2 Risk of OHSS as Failure 16/26 (61.5%) 2/13 (15.4%) 17/26 (65.4%) 2/13 (15.4%) Fisher’s Exact p = 0.008 Fisher’s Exact p = 0.006 75 IU Placebo 75 IU Placebo FDA’s Analysis FDA Background Package, Section 2.2, Table 4 Serono’s Analysis Serono Background Package, Table 6.1.1-1 Primary Analysis
  59. 59. Studies 21008 and 21415 Protocol Definition of Success <ul><li>“The primary efficacy endpoint will be follicular development as defined by the following three parameters, all of which must be true: </li></ul><ul><ul><li>At least one follicle with a mean diameter  17 mm and </li></ul></ul><ul><ul><li>Preovulatory E 2 serum level  109 pg/mL (400 pmol/L) and </li></ul></ul><ul><ul><li>Mid-luteal phase P 4 level  7.9 ng/mL (25 nmol/L) </li></ul></ul><ul><li>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.” </li></ul>
  60. 60. Study 21008 Patient 251-0001 (  10 mIU/mL) Day of hCG March 7, 2000 Serum hCG 102 mIU/mL April 4, 2000 (  7.9 ng/mL) 13.2 ng/mL P 4 Serum hCG 51 mIU/mL April 6, 2000 (  109 pg/mL) 106 pg/mL E 2 (  17 mm) 20 mm Lead Follicle
  61. 61. Efficacy Overview Extension Study 21415
  62. 62. Study Eligibility for 21415 Confirmatory Study 21008 Treatment Extension Study 21415 <ul><li>Open Label Treatment: 75 IU LH and individualized dose of FSH (75-225 IU) based on patient’s previous response </li></ul><ul><li>Consistent Primary Endpoint </li></ul>If no SAE or OHSS and not pregnant 1 Cycle Treatment Up to 3 Additional Cycles of Treatment
  63. 63. Study 21415 Patient Disposition <ul><li>31 of 39 patients in Study 21008 enrolled and treated with 75 IU r-hLH in Study 21415 </li></ul><ul><ul><li>11 Treated in 21008 with Placebo </li></ul></ul><ul><ul><li>20 Treated in 21008 with 75 IU r-hLH </li></ul></ul>Cycle 3 n=8 n=31 Cycle 1 n=31 Cycle 2 n=15
  64. 64. Study 21415 Cumulative Follicular Development with 75 IU Cycle Cancellation for Risk of OHSS is mitigated with individualization of FSH dose 21/31 26/31 27/31 With Risk of OHSS counted as Success With Risk of OHSS counted as Failure 16/31 26/31 27/31
  65. 65. Studies 21008 and 21415 Impact of Cycle Cancellation for Risk of OHSS on Response in Subsequent Cycles <ul><li>Cycle cancellation due to the Risk of OHSS is a normal precaution in clinical practice </li></ul><ul><li>Ovarian over-response is a treatment effect and provides guidance for next cycle of treatment </li></ul><ul><li>4 of the 11 patients whose cycles were cancelled due to Risk of OHSS in 1 st cycle of Study 21008 or 21415 achieved pregnancy in Study 21415 with adjustment of FSH dose in subsequent cycle </li></ul>
  66. 66. Study 21415 Sub Group: LH Naïve Patients (n=11) Follicular Development and Pregnancy 1/11 7/11 4/11 0/11
  67. 67. 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 Receiving hCG = 20/27 (74.1%) 11 Pregnancies 9 Pregnancies 0 Pregnancies
  68. 68. 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 Receiving hCG = 16/27 (59.3%) 11 Pregnancies 5 Pregnancies 0 Pregnancies
  69. 69. Summary of Pregnancy Results and Pregnancy Outcomes
  70. 70. Studies 6253, 21008 and 21415 Pregnancy Rates in Profoundly LH Deficient Women (LH < 1.2 IU/L) 1 (12.5%) 19 (39.6%) [20.9%] 0 1 (4.5%) Clinical Pregnancies n (% patients) [% cycles] 1 (12.5%) 24 (50%) [26.4%] 0 2 (9.1%) Total Pregnancies n (% patients) [% cycles] 8 91 9 22 Cycles of Treatment in Patients Seeking Pregnancy 8 48 9 22 Patients Seeking Pregnancy 225 IU LH 75 IU LH 25 IU LH Placebo/0 IU Treatment Group
  71. 71. All Studies Pregnancy Outcome for Patients Seeking Pregnancy 30 13 111 19 41 Patients Seeking Pregnancy 30 14 196 19 41 Cycles of Treatment 0 0 1 0 0 Stillbirth 0 0 2 0 1 Other 1 0 6 0 2 Miscarriage 3 1 35 1 4 Clinical Pregnancies Leading to Live Births 2 1 0 0 1 0 22 12 1 0 1 0 2 2 0 <ul><ul><li>Single </li></ul></ul><ul><ul><li>Twins </li></ul></ul><ul><ul><li>Triplets </li></ul></ul>6 2 51 2 7 Total Pregnancies 0 0 3 0 0 Lost to follow-up 4 1 44 1 5 Clinical Pregnancies 225 IU LH 150 IU LH 75 IU LH 25 IU LH Placebo/0 IU Treatment Group
  72. 72. Efficacy Conclusions
  73. 73. Efficacy Conclusions <ul><li>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) </li></ul><ul><ul><li>No benefit of 25 IU dose of r-hLH </li></ul></ul><ul><ul><li>No additional benefit of 225 IU dose of r-hLH </li></ul></ul><ul><li>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 </li></ul>
  74. 74. Efficacy Conclusions (cont’d) <ul><li>Study 21415 supports the efficacy of 75 IU as used in standard clinical practice with individualized dosing </li></ul><ul><ul><li>Cumulative follicular development rate 87.1% </li></ul></ul><ul><ul><li>Cumulative pregnancy rate 74.1% </li></ul></ul><ul><li>Overall, a 50% (24/48) pregnancy rate in profoundly LH-deficient women* (LH < 1.2 IU/L) on 75 IU dose </li></ul>* Studies 6253, 21008, and 21415
  75. 75. Overview of Safety
  76. 76. Safety Conclusions <ul><li>Largest safety database in Female HH Patients (170 patients, 152 received r-hLH in 283 cycles) </li></ul><ul><li>No increase in adverse events when r-hLH is co-administered with r-hFSH, compared to r-hFSH alone </li></ul><ul><li>Similar rates of OHSS across all dose groups, including r-hFSH alone </li></ul><ul><li>Safety profile of r-hLH comparable to currently marketed gonadotropins </li></ul>
  77. 77. Overall Conclusions Luveris ® Clinical Development Program <ul><li>Among women with HH, a cut-off value of 1.2 IU/L differentiates between LH-dependence and LH-independence </li></ul><ul><li>Follicular development is an appropriate endpoint in this population and correlates with pregnancy </li></ul><ul><li>Canceling a cycle is prudent clinical practice in an over-responding patient with follicular development </li></ul><ul><li>Women with profound LH-deficiency clearly benefit from treatment with Luveris ® 75 IU </li></ul><ul><li>The safety profile of Luveris ® is similar to other gonadotropins and is not different from treatment with FSH alone </li></ul>
  78. 78. Clinical Perspective and Risk/Benefit Assessment Nanette F. Santoro, MD Professor and Director, Division of Reproductive Endocrinology Department of Obstetrics and Gynecology and Women’s Health Albert Einstein College of Medicine
  79. 79. Hypogonadotropic Hypogonadism (HH) Women and Infertility <ul><li>Absence of pubertal development </li></ul><ul><li>Single endocrine factor </li></ul><ul><li>Potential to be highly fertile when ovarian responsiveness is restored </li></ul><ul><li>LH (in addition to FSH) is needed for optimal follicle growth </li></ul><ul><li>Induction of follicular development as a prelude to fertility is the therapeutic goal </li></ul>
  80. 80. Follicular Maturation <ul><li>FSH </li></ul><ul><li>Induces early growth </li></ul><ul><li>Controls follicle number </li></ul><ul><li>LH </li></ul><ul><li>Provides estrogen precursors </li></ul><ul><li>Needed for latter stages of growth </li></ul>
  81. 81. r-hFSH in Woman with HH: Follicle Growth Without Estradiol Follicular size (mm) r-hFSH (IU/day) 75 150 0 hCG (10,000 IU) 20 15 5 10 0 8 6 2 4 0 FSH (IU/L) LH (IU/L) Estradiol (pmol/L)
  82. 82. Risk of OHSS vs OHSS 3 Developing Follicles OHSS: Massive Ovarian Enlargement and Multiple Cysts
  83. 83. Follicular Development in HH <ul><li>Give back what’s missing </li></ul><ul><ul><li>GnRH highly effective if intact pituitary function, but not available </li></ul></ul><ul><ul><li>Alternative strategy: exogenous gonadotropins (u-hMG), but combined fixed ratio and IM administration is a limitation to treatment </li></ul></ul><ul><ul><li>Optimal strategy: stand-alone recombinant human LH and FSH allows titration and individualization </li></ul></ul>
  84. 84. Recombinant LH <ul><li>Permissive and obligatory for follicle growth </li></ul><ul><li>FSH tailoring is needed in gonadotropin cycles, therefore: rLH dose should be ‘guaranteed’ to be sufficient! </li></ul><ul><li>75 IU dose is adequate </li></ul><ul><li>Maximizes return on investment (cycle) for patient and clinician </li></ul>
  85. 85. Risks vs. Benefits <ul><li>Risks </li></ul><ul><li>Known complications of gonadotropins in infertility treatment </li></ul><ul><ul><li>Ovarian Hyperstimulation Syndrome (OHSS) </li></ul></ul><ul><ul><li>Multiple births </li></ul></ul><ul><li>Other minimal/transient treatment-related adverse events (minor) </li></ul><ul><li>Risks mitigated with proper diagnosis, dosing and observation </li></ul>
  86. 86. Risks vs. Benefits <ul><li>Benefits </li></ul><ul><li>Optimal folliculogenesis and endocrine profile based on individualized treatment </li></ul><ul><li>Convenience (subcutaneous, self-administered) </li></ul><ul><li>Safety profile comparable to currently marketed gonadotropins </li></ul><ul><li>High pregnancy rate in this profoundly LH-deficient patient population </li></ul>
  87. 87. Summary <ul><li>HH is a rare patient group for whom LH is critical during folliculogenesis </li></ul><ul><li>Provision of rLH to rFSH allows maximum flexibility in treatment of these patients </li></ul><ul><li>Benefit/risk profile in favor of approval and making product available to patients and physicians </li></ul>
  88. 88. Summary and Conclusions Pamela Williamson Joyce, RAC Vice President, Regulatory Affairs & Quality Assurance – U.S. Serono, Inc.
  89. 89. Conclusions <ul><li>Clear need for LH in treatment of patients with this rare condition </li></ul><ul><li>Appropriate patient population – HH women, profoundly LH deficient </li></ul><ul><li>Optimal dose of 75 IU safe and effective </li></ul><ul><li>Follicular development, as prospectively defined, most appropriate to determine action of LH </li></ul><ul><li>Most extensive database in r-hLH in hypogonadotropic hypogonadal women (n=170) </li></ul>
  90. 90. Conclusions <ul><li>Largest double-blind placebo-controlled clinical trial (21008) in patients with this rare condition </li></ul><ul><li>Pivotal trial positive whether cycle cancellation due to Risk of OHSS analyzed as efficacy success or failure </li></ul><ul><li>Additional supportive efficacy, safety and pregnancy data (21415) </li></ul>
  91. 91. Conclusions <ul><li>No increase in adverse events compared to placebo; safety similar to that of other gonadotropin products </li></ul><ul><li>Luveris ® is effective for treatment of infertile women with profound LH deficiency (LH < 1.2 IU/L) </li></ul><ul><li>Positive Benefit/Risk profile </li></ul>

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