Development of Personalised Infertility Treatment Robust Collaboration Between Drug and Diagnostic Developers

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1 Development of Personalised Infertility Treatment Robust Collaboration Between Drug and Diagnostic Developers Joan-Carles Arce, MD PhD Vice President, Science & Medicine, Reproductive Health Global Non-Clinical and Clinical R&D World CDx, London 17 March 2016

2 Fertility treatment by Assisted Reproductive Technologies (ART) Infertility is recognized as a disease by WHO. The estimated prevalence of infertility in developed countries is 9%. More than 1,400,000 IVF cycles are conducted annually worldwide. Gonadotropin therapy to stimulate the ovaries to produce multiple oocytes In vitro fertilisation (IVF) Embryo transfer Daily s.c. injections with gonadotropins (typically 10 days) Oocyte retrieval (typically 12 oocytes but great variation) for in vitro fertilisation Embryo culture and development Selection of the best embryo(s) for transfer to the uterus (preferably only one embryo)

3 The Clinical Problem

4 Variation of ovarian response Administration of a standard starting dose of gonadotropin to all patients results in a variety of responses, which for some patients are associated with efficacy or safety concerns. 12 Average 10.7 ± Frequency (%) of patients When using gonadotrophins for ovarian stimulation in IVF treatment use an individualised starting dose of folliclestimulating hormone, based on factors that predict success, such as: age, BMI, presence of polycystic ovaries and ovarian reserve Number of oocytes Correct identification of high and low responders has the benefit of allowing treatment to be customised. NICE fertility guideline

5 Current situation leaves room for improvement of ovarian stimulation Same starting dose of gonadotropin to all patients This approach is associated with efficacy or safety concerns for some patients Highest efficacy Number of patients Observed distribution Ideal curve Risk of low efficacy Risk of safety concerns and cancellation of transfer Number of oocytes

6 Evolution in treatment strategy Current Practice MOVE TOWARDS Personalised Medicine One dose fits all (one treatment fits all) My own experience (based on patient characteristics) Trial and error (unvalidated approach) The right treatment at the right dose for the right person 30 Jan 2015: Obama launches Precision Medicine Initiative Most medical treatments have been designed for the average patient treatments can be very successful for some patients but not for others.

7 The Biomarker

8 Anti-Müllerian Hormone (AMH) Background Member of transforming growth factor (TGF)-β superfamily. Dimeric glycoprotein, consisting of two monomers linked by disulphide bonds, with a molecular weight of 140 kda. AMH is exclusively produced by granulosa cells from primary to early antral follices not in primordial follicles or in growing follicles (making AMH a marker specific for early stages of follicle development) AMH during female life-span Absence of AMH during early female fetal development Ovarian AMH production starts around birth ( 32 weeks) AMH levels rise at the pre-pubertal years. In adult women, AMH levels decline gradually with age and become undetectable a few years before menopause. La Marca et al., Hum Reprod 2009 Seifer et al., Fertil Steril 2011 Wallace & Kelsey, PLoS One 2010 Jeppesen et al., Mol Hum Reprod 2013 Kelsey et al., PLoS One 2011 Dewailly et al., Hum Reprod 2014

9 AMH as predictor of number of oocytes and excessive and poor response to gonadotropins AMH is a quantitative marker of number of oocytes retrieved AMH is a marker of low, normal and excessive ovarian response Based on meta-analysis of 20 studies Woman s age Antral follicle count Compared to AMH AMH best AMH equal (single-centre) AMH best (multi-centre) FSH (cycle day 3) Estradiol (cycle day 3) Nelson et al., Hum Reprod 2007 Inhibin B (cycle day 3) Ovarian volume AMH best AMH best AMH best AMH best La Marca et al., Hum Reprod Update 2010

10 AMH has the best correlation to number of oocytes retrieved overall and at individual clinics Ferring has gathered data on AMH in clinical development programmes for more than 10 years AMH assay: Beckman Coulter Immunotech (GnRH agonist) trial and Gen II (GnRH antagonist trial) AMH: 0.56 (0.50; 0.62) AFC: 0.28 (0.20;0.36) AMH: 0.55 (0.50;0.60) AFC: 0.33 (0.26;0.39) Nelson & Arce, Fertil Steril 2015

11 AMH best for prediction of low and high ovarian response Ferring has gathered data on AMH in clinical development programmes for more than 10 years Sensitivity Sensitivity AMH (AUC = 0.897) FSH (AUC = 0.719) Inhibin B (AUC = 0.637) AFC (AUC = 0.741) 0.2 AMH (AUC = 0.813) FSH (AUC = 0.731) Inhibin B (AUC = 0.534) AFC (AUC = 0.636) Specificity Specificity Low response (<4 oocytes retrieved or cycle cancellation due to poor response) High response ( 15 oocytes retrieved or cycle cancellation due to excessive response) Arce et al., Fertil Steril 2013

12 The Novel Drug

13 Slides omitted due to confidential contents

14 Clinical development of FE Phase I single-dose Phase I multiple-dose Phase I bioavailability (SC/IV ) Phase II dose-response (AMH strata) Ovarian response influenced by dose, AMH and body weight PK/PD modelling and simulation + analysis of clinical trial databases + biomarkers Individualised dosing regimen based on AMH and body weight EMA Scientific Advice Different PK/PD profile with FE compared to existing rfsh preparations CHMP s Position at EMA Scientific Advice An individually tailored gonadotropin dosing regimen in a phase 3 study would be unprecedented. The Applicant has developed an algorithm in a convincing way to calculate the starting dose for patients in function of body weight and AMH. Separate clinical trials activities specific for US, Japan and China (PanAsia) are not displayed

15 The CDx Pair

16 Ovarian stimulation FE AMH CDx Collaboration Targeted Therapeutic (FE ) Companion Diagnostic (CDx) (ELECSYS AMH assay) Drug+CDx in Reproductive Health Drug+CDx on dosing Ferring Pharmaceuticals Novel gonadotrophin human cell line Differentiated PK & PD profile Extensive clinical programme Roche Diagnostics Robust AMH assay Experience in CDx regulatory Global presence Multiple platforms

17 Current AMH assay characteristics Iliodromiti et al., Hum Reprod 2014

18 Usual CDx vs the FE AMH CDx For most IVDs, the clinical implications are straight-forward Treatment vs non-treatment Response vs non-response FE AMH CDx dosing for ovarian response Assay variation Biological variation Different types of variation Link between assay variation and impact on dose and thereafter impact on response Response variation

19 Slides omitted due to confidential contents

20 Long-term partnership EU/ROW activities Collaboration initiated in phase 2 and agreement in place before pivotal phase 3 CDx trials Planning and conduct of phase 3 trials Preparation of regulatory dossiers and review by authorities Launch and post-launch To be repeated for each phase 3 trial and each region Partnership has to cover the life-span of the CDx pair

21 Regulatory collaboration CDx guidelines and regulatory requirements / pathways in all regions Joint 4-sided meetings with regulatory agencies, as needed (authorities device and drug divisions, Roche and Ferring) Overview of documents needed from Ferring and Roche for drug and IVD trials and submissions Ensure timing of when the relevant parties are to be on stand-by for input to dossier and responses to regulatory authorities Labelling cross-referencing: drug SmPC versus IVD method sheet Ensure timing of submissions and expected approvals for drug and IVD

22 Commercial collaboration Collaboration on global and local level Coordination between Ferring and Roche regarding launch timelines and activities Launch synchronization on country level is critical Elecsys AMH stand alone test (ovarian reserve) Registration Launch Ideally > 1 year Elecsys AMH CDx (companion diagnostic) Registration Launch Readiness Launch FE Submission Approval Launch Gdynia Gdansk Elecsys AMH stand alone test: assay for assessment of ovarian reserve Elecsys AMH CDx: companion diagnostic test for dose detemination of FE Wroclaw Poznan Szczecin Warszawa Lodz Rzgow Kielce Bialystok For each country coordination: o o o o Regulatory timelines Market Access timelines Product supply timelines Pricing Opole Commercial lab with Roche platform Katowice Kraków Commercial lab with competitor platform IVF center with competitor Platform used IVF center with Roche Platform used IVF center who sends out samples

23 Summary CDx FE and Elecsys AMH First CDx approach within reproductive health (fertility) and first CDx approach for dosing The CDx pair aims to improve safe use and predictability of response to the novel drug Multiple challenges / learnings for the clinical development path and the regulatory process have been encountered o o Integration of CDx strategy during development Clinical/regulatory argumentation Collaboration across functions between diagnostics company and pharma company is required to meet the development, regulatory and commercial objectives