# Presentation: 200381

## Reproductive HealthAdvisory CommitteeSeptember 30, 2003 

**Pamela Williamson Joyce, RAC**
**Vice President, Regulatory Affairs****& Quality Assurance – US****Serono, Inc.**

**NDA ****#****21-322**

## 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**** **

## Agenda

| Introduction and Regulatory History | Pamela Williamson Joyce, RAC
Vice President, Regulatory Affairs & Quality Assurance – US
Serono, Inc. |
| --- | --- |
| Need for and Role of LH: HH Women with Profound  Gonadotropin Deficiency | Jerome Strauss, M.D., Ph.D.
Luigi Mastroianni Jr. ProfessorDirector, Center for Research on Reproduction and Women’s Health
University of Pennsylvania |
| Luveris® Clinical Development Program | Paul Lammers, M.D.
Chief Medical OfficerSerono, Inc. |
| Clinical Perspective and Risk/Benefit Assessment | 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 |
| Summary and Conclusions | Pamela Williamson Joyce, RAC
Serono, Inc. |

## Luveris® (lutropin alfa for injection)

**Luteinizing hormone produced by recombinant DNA technology**
**Common names**
- Recombinant human luteinizing hormone
- r-hLH
**Lyophilized powder in 75 IU vials**
**Self-administered by subcutaneous injection**

## Currently Approved in 46 Countries 

| Argentina |  | Greece | Peru |
| --- | --- | --- | --- |
| Australia |  | Guatemala | Poland |
| Austria |  | Holland | Portugal |
| Belgium |  | Hong Kong | Romania |
| Brazil |  | Hungary | Singapore |
| Bulgaria |  | Iceland | Slovak Republic |
| Chile |  | Ireland | Slovenia |
| Colombia |  | Israel | Spain |
| Costa Rica |  | Italy | Sri Lanka |
| Czech Republic |  | Latvia | Sweden |
| Denmark |  | Lithuania | Switzerland |
| Dominican Republic |  | Luxemburg | Trinidad & Tobaggo |
| Estonia |  | Mauritius | United Kingdom |
| Finland |  | Mexico | Uruguay |
| France |  | Norway | Venezuela |
| Germany |     |  |  |

## Orphan Drug Designation for Luveris®

| “For use in association with recombinant human follicle stimulating hormone for the treatment of women with chronic anovulation due to hypogonadotropic hypogonadism” |  |
| --- | --- |
| Orphan Drug Regulation | Provides incentive for the development of drugs to treat rare diseases and conditions |
| Rare Disease or Condition | Prevalence < 200,000 patients with the disease in the US |
| Prevalence | Hypogonadotropic Hypogonadal Women2,800-5,600 (1/50,000-1/25,000)* |

*** OOPD ****#****94-802**

## Regulatory History – Luveris®Clinical Development Program

| May 1992 | Pre-IND Meeting - clinical program of r-hLH for follicular development
2 Phase II/III Studies (6253, 6905) |
| --- | --- |
| March 1999 | Studies completed – 2 different populations – insufficient for NDA filing
Confirmatory Phase III trial (Study 21008) required for approval |
| December 2000 | Pre-NDA meeting with FDA Division of Reproductive and Urologic Drug Products |
| April 2001 | NDA submitted to FDA |

## Regulatory History – Luveris®  (cont’d)Clinical Development Program

| March 2002 | Not Approvable Letter
Insufficient evidence to support efficacy of the 75 IU/day dose
Conduct another Phase III study
Efficacy vs. Placebo
Ovulation induction
Dose ranging
Placebo, 75 IU and lower dose (50 or 25 IU) |
| --- | --- |
| April 2002 | Type A meeting – cycle cancellation due to Risk of OHSS |
| January 2003 | FDA will bring Luveris® before Advisory Committee |

## Regulatory History – Luveris®  (cont’d)Clinical Development Program

| April 2003 | NDA amended to include results from extension study (21415) for confirmatory phase III trial |
| --- | --- |
| August 2003 | NDA amended to revise indication |

## Topics for Discussion

**Is there a need for recombinant luteinizing hormone?**
**Has the appropriate patient population been defined?**
**Has a safe and effective dose been identified?**
- 75 IU/day
**Is the composite primary endpoint of follicular development an appropriate endpoint to assess efficacy in this patient population?**

## Topics for Discussion (cont’d)

**Is the definition of treatment success appropriate?**
- Primary efficacy endpoint
- Follicular development
- Cancellation for the *Risk* of OHSS
- Pregnancy
- Serum -hCG pregnancy test and/or ultrasound
**Do the data support the safety and efficacy of Luveris****®**** in the proposed indication?**
**Should another phase III double-blind ****placebo-controlled clinical trial be required for approval of Luveris****®**** in patients with this rare condition?**

## External Consultant Experts

**Sarah L. Berga, MD**
- James Robert McCord Professor and ChairDepartment of Gynecology and ObstetricsEmory University School of Medicine
**Michael Diamond, MD**
- Kamram S. Moghissi Professor and Associate Chair of Obstetrics and Gynecology,Director, Division of Reproductive Endocrinology & InfertilityWayne State University (Detroit, MI)
**Gary Koch, PhD**
- Statistical ConsultantChapel Hill, NC

## External Consultant Experts (cont’d)

**Bert Spilker, MD, PhD**
- Co-founder and former PresidentOrphan Medical
- 	Adjunct Professor of Medicine; Clinical Professor of PharmacyUniversity of North Carolina (Chapel Hill, NC)
**Nanette F. Santoro, MD**
- Professor and Director, Division of Reproductive Endocrinology
- 	Department of Obstetrics and Gynecology and Women’s HealthAlbert Einstein College of Medicine (NY)
**Jerome Strauss, MD, PhD**
- Luigi Mastroianni Jr Professor
- 	Director, Center for Research on Reproduction and Women’s HealthUniversity of Pennsylvania
- 	Associate Chairman, Department of Obstetrics and Gynecology

## 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**

## Outline

**Heterogeneity of pathophysiology and phenotype in Hypogonadotropic Hypogonadism (HH)**
**Consequences of profound LH deficiency**
**Current therapeutic options for HH**
**Unmet medical need**

## HH Can Be Caused by Hypothalamic Disorders, Pituitary Disease or Both

**HH Can Be Caused by Hypothalamic Disorders, Pituitary Disease or Both**

**Hypothalamus**

**Pituitary**

**Ovary**

## HH:  A Rare, Heterogeneous Condition

**Pathophysiology**
**Congenital**
**Acquired**
**Variable deficiency**
- Pan-hypopituitarism
- Isolated gonadotropin deficiency
- Moderate impairment

## Diagnosis of Profound LH Deficiency in HH

**Serum LH levels < 1.2 IU/L**
- Shoham Z et al. *Fertil Steril* 1991; 56:1048-1053
**Endocrine or functional evidence of estradiol deficiency**
- Estradiol level <30 pg/ml
- Failed progestin challenge test

## Outline

**Heterogeneity of pathophysiology and phenotype in Hypogonadotropic Hypogonadism (HH)**
**Consequences of profound LH deficiency**
**Current therapeutic options for HH**
**Unmet medical need**

## Role of LH in Ovarian Function

**Follicular steroidogenesis**
- Stimulation of androgen synthesis by theca cells
**Follicular maturation**
- Can support terminal stages of follicular maturation
**Ovulation**
- Resumption of meiosis
- Ovulation
- Luteinization
**Maintenance of luteal function**

## LH and FSH Action on the Follicle

**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**

## Ovarian Defects in LH Receptor KO Mice

**Zhang et al. *****Mol Endocrinol*****. 15:172-183, 2001.**

## HH Treated with r-hFSH Alone

**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)**

## HH Treated with r-hFSH and r-hLH

**HH Treated with r-hFSH and r-hLH**

**Estradiol**
**(pg/ml)**

**Serono data Study 6253**

## The LH Therapeutic Window Concept

**Balasch J, F****ábreques F. *****Curr Opin Obstet Gynecol***** 2002, 14:265-274**

## Outline

**Heterogeneity of pathophysiology and phenotype in Hypogonadotropic Hypogonadism (HH)**
**Consequences of profound LH deficiency**
**Current therapeutic options for HH**
**Unmet medical need**

## Current Therapeutic Options for HH

**Gonadotropin Releasing Hormone (GnRH)**
**Pro**
- Effective in women with hypothalamic disease and intact pituitary
- Monofollicular ovulation
**Con**
- Approved but discontinued
- Requires long-term pulsatile infusion

## Current Therapeutic Options for HH

**Human Menopausal Gonadotropins (hMG)**
**Pro**
- Reported to be effective in mostly small, uncontrolled series
- Can be used in women with hypothalamic and/or pituitary disease
**Con**
- Fixed ratio of FSH and LH
- Ovarian Hyperstimulation Syndrome (OHSS)
- Multiple gestation

## Outline

**Heterogeneity of pathophysiology and phenotype in Hypogonadotropic Hypogonadism (HH)**
**Consequences of profound LH deficiency**
**Current therapeutic options for HH**
**Unmet medical need**

## Unmet Medical Need

**No FDA approved LH-only treatment for profoundly LH deficient patients**
**Individualization/titration**
- No options available for individualization of treatment
**Recombinant Product**
- Purity
- Consistency
- S.C. administration

## Conclusions		

**LH is required for follicular competency**
**HH is a very rare, heterogeneous disorder**
**HH women profoundly deficient in LH require exogenous LH for normal follicular function**
**Optimal therapy of HH is based on individualized treatment**

## Luveris® Clinical Development Program

**Paul Lammers, MD**
**Chief Medical Officer****Serono, Inc.**

## Presentation Outline

**Luveris****®**** (r-hLH) Clinical Development Program**
- Study Design Considerations
- Study Endpoints & Definition of Treatment Effect
**Dose Finding Studies **
**Efficacy Overview**
- Confirmatory Phase III Study 21008
- Extension Study 21415
- Pregnancies & Pregnancy Outcomes
**Safety Overview**
**Overall Conclusions**

## Clinical Development Program of Luveris®

*** Fixed Dose of 150 IU r-hFSH**

| Study | Description | Population | No. of Patients | r-hLH Doses (IU) |
| --- | --- | --- | --- | --- |
| 6253* | Dose Finding | Profoundly LH / FSH deficient | 38 | 0, 25, 75, 225 |
| 7798* | Dose Response, Uncontrolled | Profoundly LH / FSH deficient | 15 | 75, 150, 225 |
| 21008* | Confirmatory, Double-Blind | Profoundly LH / FSH deficient | 39 | Placebo, 75 |
| 21415 | Extension               to 21008 | Profoundly LH / FSH deficient | 31 | 75   |
|  |  |  |  |  |
| 6905* | Dose Finding | Hypo / hypo | 40 | 0, 25, 75, 225 |
| 8297* | Sequential Dosing, Uncontrolled | Hypo / hypo | 38 | 75, 150, 225 |

## Design ConsiderationsDose Finding Studies and Confirmatory Study 21008

**Study design considerations**
- Identify a clear dose response
- Focus on effect of LH treatment only
- Avoid potential confounder:  change in FSH dose
- Fix the dose of LH and FSH in each cycle
**Clinical considerations**
- Absence of pre-existing data in this population
- Provide adequate starting dose of FSH (150 IU)
- Conservative criteria for discontinuing treatment for ovarian over-response (*Risk* of OHSS)

## Primary Composite Efficacy Endpoint: Capture Various Actions of LH 

**Synergistic Action of LH with FSH on ****Follicular Growth**
- Follicle size  17 mm
- Normal pre-ovulatory size
**Necessary Role of LH in Enabling ****Follicular Function**
- Serum E2  109 pg/ml (400 pmol/L)
- Lower limit of normal, and adequate for endometrial response
**Contribution of LH to Corpus Luteum Competence, after hCG Administration**
- Mid-luteal P4  7.9 ng/ml (25 nmol/L)
- Above threshold for normal ovulating women( 6.0 ng/mL)

## Definition of Treatment Success

**Composite Endpoint – Follicular Development**
- 1.  At least one follicle  17 mm in diameter
- 2.  Pre-ovulatory Serum Estradiol  109 pg/ml (400 pmol/L)
- 3.  Mid-luteal Phase Serum P4  7.9 ng/ml (25 nmol/L)
***OR***
**Pregnancy****Positive ********-hCG**** (>10 mIU/mL) or confirmatory ****Ultrasound**
***OR***
**Cycle Cancellation for *****Risk***** of OHSS**
**Ovarian Response:**** 3 follicles ******** 15 mm and/or E****2**** level >1100 pg/ml**

## Key Secondary Efficacy Endpoints

**Estradiol (E****2****) level**
**Endometrial thickness (mm)**
- Receptive uterine ‘milieu’
**Pregnancy Rate**

## Dose Finding Studies

**Study 6253 and Study 6905 **

## Study 6253Study Design

**Controlled, parallel-designed, open-label, randomized, ****3 cycle, dose-finding**
- Multinational study: September 1993 - April 1995
- 38 subjects enrolled in 10 centers in 4 countries
**Standard dose-finding approach**
- r-hFSH: 150 IU per day
- r-hLH: 0, 25, 75, and 225 IU per day (1:1:1:1 in Cycle 1)
- Protocol pre-specified an Armitage trend test to detect relationship between the LH dose and follicular development in Cycle 1
**Adequately powered at 85%**

## Study 6253Study Design (cont’d)

**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 response was ongoing (E2 rise and follicle > 10 mm), treatment could continue beyond 14 days
**Primary and secondary endpoints to be analyzed ****in cycle 1**
**Pregnancy rates to be evaluated across all 3 cycles**

## Study 6253Study Population

| Diagnosis | No. of Patients |
| --- | --- |
| Primary Amenorrhea
Kallmann Syndrome
Idiopathic, isolated HH
Trauma- or tumor-related isolated gonadotropin deficiency
Multiple pituitary deficiencies | 7
14
1
6 |
| Secondary Amenorrhea
Functional or idiopathic isolated gonadotropin deficiency
Trauma- or tumor-related multiple pituitary deficiencies | 8
2 |
| Total | 38 |

**Study 6253****Study Population**

## 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 **

## Study 6253Results for Patients Randomized to 225 IU in Cycle 1

**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**

## Study 6253Secondary Efficacy Parameters – Cycle 1

**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**

## 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**

## Study 6905Study Design (cont’d)

**Major Differences to Study 6253**
- LH < 13 IU/L and FSH < 11 IU/L*
- Broader HH population
- No progestin challenge test; E2 < 60 pg/mL
- Treatment duration up to 21 days
- If follicular maturation was imminent, treatment could continue beyond 21 days

*** <50****th**** percentile normal**

## 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**

## 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**

## Lowest Effective Dose

**Reasonable and sufficient range of doses studied****(0, 25, 75, and 225 IU)**
**25 IU dose**
- Not clinically/statistically different from 0 IU
- 75% non-response
**75 IU dose**
- Clinically/statistically different from 0 IU in primary endpoint (more than a five-fold increase in patient response)
- Clinically different from 0 IU in secondary endpoints (E2 levels, and endometrial response)
**225 IU dose**
- No additional benefit in efficacy compared to 75 IU

***75 IU is the minimum effective dose providing maximum therapeutic benefit***

## 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**

## Efficacy Overview

**Confirmatory Phase III Trial **
**Study 21008**

## 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**

## Study 21008Study Design (cont’d)

**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)**

## 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 |
| Total | 39 |

## 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***

## 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**

## Study 21008Comparison of Analyses – Follicular Development

## 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.”**_

## Study 21008Patient 251-0001

| Lead Follicle | 20 mm | ( 17 mm) |
| --- | --- | --- |
| E2 | 106 pg/mL | ( 109 pg/mL) |
| P4 | 13.2 ng/mL | ( 7.9 ng/mL) |
| March 7, 2000 | Day of hCG |  |
| April 4, 2000 | Serum hCG 102 mIU/mL | ( 10 mIU/mL) |
| April 6, 2000 | Serum hCG 51 mIU/mL |  |

## Efficacy Overview

**Extension Study 21415**

## Study Eligibility for 21415

**Confirmatory**
**Study 21008**

**Treatment Extension**
**Study 21415**

**Open Label Treatment:****75 IU LH and individualized dose of FSH (75-225 IU) based on patient’s previous response**
**Consistent Primary Endpoint**

**If no SAE or OHSS **
**and not pregnant **

**1 Cycle Treatment**

**Up to 3 Additional Cycles**
**of Treatment**

## Study 21415Patient Disposition

**Study 21415****Patient Disposition**

**31 of 39 patients in Study 21008 enrolled ****and treated with 75 IU r-hLH in Study 21415**
**11 Treated in 21008 with Placebo**
**20 Treated in 21008 with 75 IU r-hLH**

## 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***

## 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 1****st**** cycle of Study 21008 or 21415 achieved pregnancy in Study 21415 with adjustment of FSH dose in subsequent cycle**

## Study 21415Sub Group:  LH Naïve Patients (n=11)Follicular Development and Pregnancy

**Study 21415****Sub Group:  LH Naïve Patients (n=11)****Follicular Development and Pregnancy**

**1/11**

**7/11**

**4/11**

**0/11**

## 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**

## 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**

## Summary of Pregnancy Results and Pregnancy Outcomes

## Studies 6253, 21008 and 21415 Pregnancy Rates in Profoundly LH Deficient Women (LH < 1.2 IU/L)

| Treatment Group | Placebo/0 IU | 25 IU LH | 75 IU LH | 225 IU LH |
| --- | --- | --- | --- | --- |
| Patients Seeking Pregnancy | 22 | 9 | 48 | 8 |
| Cycles of Treatment in Patients Seeking Pregnancy | 22 | 9 | 91 | 8 |
| 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%)
 |

## All StudiesPregnancy Outcome for Patients Seeking Pregnancy

| Treatment Group | Placebo/0 IU | 25 IU LH | 75 IU LH | 150 IU LH | 225 IU LH |
| --- | --- | --- | --- | --- | --- |
| Patients Seeking Pregnancy | 41 | 19 | 	111 | 13 | 30 |
| Cycles of Treatment | 41 | 19 | 	196 | 14 | 30 |
| Total Pregnancies  | 7 | 2 | 	51 | 2 | 6 |
| Clinical Pregnancies  | 5 | 1 | 	44 | 1 | 4 |
| Clinical Pregnancies  Leading to Live Births | 4 | 1 | 	35 | 1 | 3 |
| Single
Twins
Triplets | 2
2
0 | 0
1
0 | 	22
	12
	1 | 0
1
0 | 2
1
0 |
| Miscarriage | 2 | 0 | 	6 | 0 | 1 |
| Lost to follow-up | 0 | 0 | 	3 | 0 | 0 |
| Other | 1 | 0 | 	2 | 0 | 0 |
| Stillbirth | 0 | 0 | 	1 | 0 | 0 |

## Efficacy Conclusions

## 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**

## Efficacy Conclusions (cont’d)

**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**

## Overview of Safety 

## 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**

## 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**

## 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**

## 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**

## Follicular Maturation

**FSH**
**Induces early growth**
**Controls follicle number**
**LH**
**Provides estrogen precursors**
**Needed for latter stages of growth**

## r-hFSH in Woman with HH: Follicle Growth Without Estradiol

**Follicular size****(mm)**

**r-hFSH****(IU/day)**

- <date/time>

## Risk of OHSS vs OHSS

**3 Developing Follicles**

**OHSS: Massive Ovarian Enlargement and Multiple Cysts**

## Follicular Development in HH

**Give back what’s 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

## Recombinant LH

**Permissive and obligatory for follicle growth**
**FSH tailoring is needed in gonadotropin cycles, therefore: rLH dose should be ‘guaranteed’ to be sufficient! **
**75 IU dose is adequate**
**Maximizes return on investment (cycle) ****for patient and clinician**

## Risks vs. Benefits

**Risks**
**Known complications of gonadotropins in infertility treatment**
- Ovarian Hyperstimulation Syndrome (OHSS)
- Multiple births
**Other minimal/transient treatment-related ****adverse events (minor)**
**Risks mitigated with proper diagnosis, ****dosing and observation**

## Risks vs. Benefits

**Benefits**
**Optimal folliculogenesis and endocrine profile based on individualized treatment**
**Convenience (subcutaneous, self-administered)**
**Safety profile comparable to currently marketed gonadotropins**
**High pregnancy rate in this profoundly ****LH-deficient patient population**

## Summary

**HH is a rare patient group for whom LH is *****critical***** during folliculogenesis**
**Provision of rLH to rFSH allows maximum flexibility in treatment of these patients**
**Benefit/risk profile in favor of approval and making product available to patients and physicians**

## Summary and Conclusions

**Pamela Williamson Joyce, RAC**
**Vice President, Regulatory Affairs****& Quality Assurance – U.S.****Serono, Inc.**

## Conclusions

**Clear need for LH in treatment of patients with this rare condition**
**Appropriate patient population – HH women, profoundly LH deficient**
**Optimal dose of 75 IU safe and effective**
**Follicular development, as prospectively defined, most appropriate to determine action of LH**
**Most extensive database in r-hLH in hypogonadotropic hypogonadal women (n=170)**

## Conclusions

**Largest double-blind placebo-controlled clinical trial (21008) in patients with this rare condition**
**Pivotal trial positive whether cycle cancellation due to *****Risk***** of OHSS analyzed as efficacy success or failure**
**Additional supportive efficacy, safety and pregnancy data (21415)**

## Conclusions

**No increase in adverse events compared ****to placebo; safety similar to that of other gonadotropin products**
**Luveris****®**** is effective for treatment of infertile women with profound LH deficiency ****(LH < 1.2 IU/L)**
**Positive Benefit/Risk profile**