Antonio Capalbo. G.EN.E.R.A, Reproductive Medicine Centers GENETYX, Molecular Genetics Laboratory Rome, Italy

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1 Antonio Capalbo G.EN.E.R.A, Reproductive Medicine Centers GENETYX, Molecular Genetics Laboratory Rome, Italy Declared receipt of Grant for fertility innovation 2013 from Merck Serono.

2 Advances in preimplantation genetic screening ANTONIO CAPALBO

3 Agenda Impact of aneuploidies in human reproduction and the role of PGS; Evidences of clinical effectiveness of blastocysts stage CCS: Preclinical validations Clinical validations in RCTs and systematic reviews; Cost effectiveness Future challenges Decreasing aneuploidy screening costs Enhance selection of euploid blastocysts

4 The most pressing issue in contemporary embryology is to enhance embryo selection The current selection of embryos to transfer based on non-invasive evaluation of morphological parameters is relatively not effective. In the Advanced Maternal Age population (36-43 years): ~ 30% cumulative clinical pregnancy rate; ~ 30% miscarriage rate; ~ 20% multiple pregnancy rate; ~ 10% of transferred embryos delivered. Ubaldi et al., HR in press

5 Blastocyst transfer enhance embryo selection but still not enough Cochrane review of 12RCTs 29,4% 36,0% NO DIFFERENCE IN MULTIPLE PREGNANCY RATE AND MISCARRIAGE RATE (13 RCTS, OR 1.18, 95% CI 0.86 TO 1.60) PER COUPLE BETWEEN THE TWO TREATMENT GROUPS (16 RCTS, OR 0.92, 95% CI 0.71 TO 1.19) live birth rate/et Adapted from Glujovsky, et al. Cochrane Review, 2012.

6 % Aneuploid Impact of aneuploidies in human reproduction Stimulated Cycles: Incidence of embryonic aneuploidy Natural Conceptions: Incidence of Trisomy in Miscarriage Specimens Aneuploidies in prenatal diagnosis (Villo or Amnio) Female Age Imp. failure Miscarriages

7 Morphology can not be relied on to ensure the transfer of chromosomally normal embryos (Capalbo et al., HR, 2014)

8 ADVANCES in PGS: Blastocyst biopsy and 24 chromosome aneuploidy screening technologies PGS v.1.0 9chromosome FISH PGS v 2.0 CCS techniques Single cell analysis issues Limited chromosome screening More cells for genetic analysis 24 chromosomes screening

9 Preclinical evidences of blastocyst biopsy and Comprehensive chromosome screening (CCS) effectiveness No impact of TE biopsy on blastocyst implantation (Prospective Paired Study Scott et al., 2013) Sustained implantation rate No major diagnostic impact of chromosome mosaicism at the blastocyst stage (Capalbo et al.,hr 2013); High positive and negative clinical predictive value of TE biopsy and CCS (Prospective Non selection Study, Scott et el., 2013); Biopsy Control High reliability of blastocyst stage aneuploidy screening (Prospective double blinded study, Capalbo et al., EJHG 2014). 1 TE biopsy + acgh 99.4% consistency 2 TE biopsy + qpcr

10 Implantation and pregnancy rates for PGD-A randomized controlled trials of young patients: data from a Systematic Revie DET Lee et al., Human Reproduction 2015

11 Implantation and pregnancy rates for PGD-A on women of advanced maternal age: data from a Systematic Review DET Lee et al., Human Reproduction 2015

12 Moving toward eset for all IVF patient population 1 2

13 Birthweight (Grams) Better obstetrical outcomes are attained after CCS/eSET than conventional two embryo transfer Mean birthweight: g Single euploid g 2-Blastocyst (P<0.001) Low Birthweight (<2,500g): 4.4% (2/45) Single Euploid 31.9% (22/69) 2-Blastocyst (P<0.001) 1000 Single euploid blastocyst transfer Grams Untested 2- blastocyst transfer Grams Very low birthweight (<1,500g): 0% (0/45) Single Euploid 7.2% (5/69) 2-Blastocyst (P=0.06) Forman EJ et al. 2014

14 Neonatal Intensive Care Unit (NICU) Admissions following eset versus DET RCT N=179 Increased risk of NICU admission Increased duration of stay in NICU Increase duration of neonatal hospital admission Forman et al AJOG 2014

15 Overall results of our PGD-A program (Genera Centers ) 1157 started cycles (Female age 39.7) In 23,9% of cycles were produced no blastocysts (276/1157) 37,6% of cycles with biopsy resulted in all aneuploid blastocysts (313/881) 601 embryo transfers performed 616 blastocysts transferred (1,02) Similar cumulative delivery rate per started cycle between PGS and standard care (21.3 versus 20.9) Ubaldi et al., Human Reproduction, In press)

16 Consistent and reproducible laboratory and clinical outcomes of PGS cycles at GENERA centres 67,9% Rome Marostica Naples TOT N=432 N=64 N=58 58,8% 60,7% 52,1% 53,4% 47,1% 45,1% 45,1% 10,0% 10,5% 9,9% 11,0% 6,1% 6,8% 9,3% 0,0% positive pregnancy test biochemical pregnancy miscarriage ongoing prengnacy Capalbo et al., Under review

17 Obstetrical Costs for 100 Patients Current Standard Of Care Costs per Delivery* Singleton $21,458 Twins $104,831 Triplets $407,199 Does not include: Pediatric costs after 28 days of age Disability costs during bed rest Loss of productivity in the work place Lemos et al Am J Obstet Gynecol 2013; 209:586

18 Overall Cost to Provide Care CCS with SET versus Conventional Treatment Use actual cost data Costs per Delivery* $80 $70 Inclusive of all IVF costs including IVF cycle costs CCS costs Medication costs $60 $50 $40 $30 Delivery costs and subsequent hospital stay through 28 days of life $20 $10 $0 CCS / SET National Avg Regional Avg Clinical data from RMA NJ. Courtesy of Dr. Scott

19 Advances in PGS Blastocysts stage CCS is an already validated technology to improve clinical outcomes per transfer during IVF in terms of higher implantation rate and reduced miscarriage rate. All SET Minimize miscarriages Avoid chr. abnormal preg. Reduced efforts, times and costs Limits Need experienced and equipped IVF laboratory to work effectively

20 Future challenges: Whole genome amplification CGH and acgh in PGD qpcr- CCS Decreasing aneuploidy screening costs; SNP array NGS and new qpcr platforms % of euploid blasts still fail! Enhance selection of euploid blastocysts excellent good average poor

21 Thanks for your attention GENERA, Centro di Medicina della Riproduzione Direttore Clinico: Filippo Maria Ubaldi Direttore di Laboratorio: Laura Francesca Rienzi GENETYX, Laboratorio di genetica molecolare Direttore di Laboratorio: Antonio Capalbo Consulente genetista: Daniela Zuccarello Biologi: Cristina Patassini Danilo Cimadomo Cristina Poggiana Emiliano Scepi Anna Cecchele

22 Key slide Blastocysts stage CCS is an already validated technology to improve clinical outcomes per transfer during IVF in terms of higher implantation rate and reduced miscarriage rate. Still needed RCTs to evaluate live birth rate per cycle. Selection of chromosomally normal embryos makes SET an effective solution for all patients undergoing IVF. Emerging technologies will briefly reduce the cost of PGS and increase the patient population that can benefit from aneuploidy screening in IVF. The increase in usage of blastocyst culture and freeze all approach will further stimulate the application of this embryo selection technology in IVF.