Presented at Fall Clinical Dermatology Conference® 2017 | Las Vegas, NV, USA | 12–15 October, 2017 | Previously presented at EADV 2017 – Sensitivity: >10 times more sensitive than the previous assay used in other CZP PK studies (lower limit of quantification [LLOQ]: 0.032 µg/mL).8 – Specificity: Requires binding of CZP to TNF and detection with an anti-PEG antibody.8 • The presence of anti-CZP antibodies in blood was determined using a previously validated enzyme-linked immunosorbent assay (ELISA). Samples were defined as positive if anti-CZP antibody levels were >2.4 units/mL.9 Study Assessments • Blood samples were collected from the mothers, umbilical cords, and infants at delivery, and from infants again at Weeks 4 and 8 post-delivery (Figure 1). • Safety analyses included all mothers who received at least one dose of CZP, and the infants of participating mothers. Adverse events (AEs) were coded according to the MedDRA v18.1. Statistical Analyses • No formal sample size calculations were performed, as no statistical hypotheses were tested. All PK variables were based on the observed values; no imputation for missing data was used. RESULTS Baseline Characteristics • 21 CZP-treated pregnant women were screened; 5 women discontinued screening. Based on preliminary PK and safety analyses, which showed consistent data for the initial mother/infant pairs enrolled, the study concluded with a final enrollment of 16 pregnant women, which was deemed sufficient to assess the primary objective. • Of the 16 mothers who entered the sampling period, 15 were on CZP 200 mg Q2W and 1 on 400 mg Q4W (Table 1). • The gestational age and weight at birth of the 16 infants were within the expected range for healthy infants (Table 1). BACKGROUND • Women affected by chronic inflammatory diseases, such as psoriatic disease, need effective and safe treatments during pregnancy.1,2 • Adequate disease control is important to reduce the risk of adverse pregnancy outcomes.3 • Anti-TNFs are efficacious, but because most cross the placenta, treatment is often stopped during pregnancy.4,5 • Certolizumab pegol (CZP), due to its Fc-free molecular structure, is not expected to undergo active placental transfer compared to other antibody-based anti-TNFs.6,7 • CRIB (NCT02019602) is the first prospective, industry-sponsored study designed to evaluate placental transfer of CZP from the mother to her infant. METHODS Patients and Study Design • CRIB was a pharmacokinetic (PK) study of pregnant women receiving commercial CZP for an approved indication. • The primary endpoint was the concentration of CZP in the infants’ plasma at birth (Figure 1). • Key inclusion criteria: – Patients were ≥30 weeks pregnant with a singleton or twins at the time of informed consent. – Patients were being treated with CZP as per the locally approved label and prescriber’s discretion. – Patients started or decided to continue CZP treatment independently from and prior to participating in this study and in accordance with the treating physician. – Patients received a CZP dose within 35 days prior to delivery. • Key exclusion criteria: – Patients had any pregnancy-related, clinically significant abnormality noted on obstetric ultrasound or other imaging assessment, or had significant laboratory abnormalities during their pregnancy. – Patients were taking or had taken any medication with strong positive evidence of human fetal risk of teratogenicity during pregnancy. – Patients had received treatment with any biological therapeutic agent, including anti-TNFs other than CZP, during pregnancy. Detection of CZP and Anti-CZP Antibodies • CZP concentrations in blood were measured using a highly sensitive, CZP-specific electrochemiluminescence immunoassay (Figure 2): References 1. Chakravarty E. et al. BMJ Open 2014;4:e004081; 2. de Man Y. et al. Arthritis Rheum 2009;60(11):3196–3206; 3. Mouyis M. et al. J Rheumatol 2017;44:128–129; 4. Ng S. et al. Expert Rev Clin Immunol 2013;9(2):161–173; 5. Østensen M. et al. Curr Opin Pharmacol 2013;13(3):470–475; 6. Mahadevan U. et al. Clin Gastroenterol Hepatol 2013;11(3):286–292; 7. Förger F. et al. Joint Bone Spine 2016;83:341–343; 8. Smeraglia J et al. Bioanalysis 2017;9(16):1217–1226; 9. Wade J. et al. J Clin Pharmacol 2015;55(8):866–874; 10. Clowse M. et al. Arthritis Rheumatol 2017;69(suppl 10):Abstract 1309. Author Contributions Substantial contributions to study conception/design, or acquisition/analysis/interpretation of data: ABK, XM, BA, AF, FF, AM, R-MF, AvT, LS, JS, MT, EH, MW, EC; Drafting of the publication, or revising it critically for important intellectual content: ABK, XM, BA, AF, FF, AM, R-MF, AvT, LS, JS, MT, EH, MW, EC; Final approval of the publication: ABK, XM, BA, AF, FF, AM, R-MF, AvT, LS, JS, MT, EH, MW, EC. Disclosures ABK: Consultant for: UCB Pharma, Dermira, Janssen, AbbVie; XM: Grant/research support: Biogen, Pfizer, UCB Pharma; Consultant for: BMS, GSK, LFB, Pfizer, UCB Pharma. BA: Grant/research support: Janssen, UCB Pharma; Speaker’s fees: AbbVie, American Reagent, Janssen, UCB Pharma. AF: Grant/research support: UCB Pharma. FF: Grant/research support: UCB Pharma; Speaker’s fees: Mepha, Roche, UCB Pharma. AM: Grant/research support: MSD, AbbVie, Pfizer, UCB Pharma; Consultant for: MSD, AbbVie, Pfizer, UCB Pharma. R-MF: Consultant for: UCB Pharma. AvT: Grant/ research support: Pfizer, AbbVie, UCB Pharma, Janssen-Cilag, Celgene, Novartis, MSD; Speaker’s fees: MSD, Janssen-Cilag, Pfizer; Consultant for: AbbVie, Novartis, Janssen-Cilag, Pfizer. LS, JS, MT, EH, MW: Employee of UCB Pharma. EC: Grant/research support: UCB Pharma. Acknowledgements This study was funded by UCB Pharma. We are indebted to the mothers and their infants for their altruistic participation. We thank the nurses, investigator teams, and Nicole Hurst (PPD), and acknowledge Cécile Ecoffet and Simone E. Auteri (UCB Pharma) for publication coordination. Editorial services for this poster were provided by Costello Medical Consulting. All costs associated with the development of this poster were funded by UCB Pharma. n (%)a Mothers (n=21)b Infants (n=16) Any TEAEs 15 (71.4) 5 (31.3) Severe TEAEs 2 (9.5) 1 (6.3) Discontinuation due to TEAEs 2 (9.5) 0 Drug-related TEAEs 3 (14.3) 1 (6.3) Serious TEAEsc 7 (33.3) 2 (12.5) Deaths 0 0 Serious TEAEs by mother-infant pair SF Placental insufficiency Premature baby N/A 1 Arrested labor None 2 Arrested labor None 3 Prolonged labor None 4 Gestational diabetes Polyhydramnios None 5 None Hypoglycemia Infection 6 Perineal abscess None 7 Vaginal laceration Macrosomia Meconium in amniotic fluid TEAEs were defined as any AE captured from the time of informed consent until the Safety Follow- Up; bold text indicates severe TEAEs. aNumber of mothers or infants reporting at least one AE for the indicated category; bSafety set for mothers (includes 5 screen failures); cSerious TEAEs were classified using the FDA definition of serious AEs. TEAE: treatment-emergent adverse event; SF: screen failure; N/A: not applicable. Table 2. Safety overview Figure 2. CZP-specific immunoassay aThe SULFO-TAG label emits light upon electrochemical stimulation initiated at the electrode surface. PEG: polyethylene glycol; Fab’: fragment antigen-binding; TNF: tumor necrosis factor. Median (min, max), unless stated otherwise Mothers (n=16)a Age, years 31 (18, 40) Mother’s indication for CZP treatment, n Rheumatoid arthritis 11 Crohn’s disease 3 Psoriatic arthritis 1 Axial spondyloarthritis/ankylosing spondylitis 1 Delivery type, n Vaginal 14 Cesarean section 2 Median (min, max), unless stated otherwise Infants (n=16) Female, n (%) 10 (62.5) Gestational age at birth, weeks 39.9 (37.7, 41.7) Weight at birth, kg 3.3 (2.6, 4.0) Length at birth,b cm 49.5 (46.0, 55.9) Normal APGAR score (7 to 10) at 1 and 5 minutes,c n 16 aMothers who entered the sampling period; bn=15 (1 infant with missing data); cAPGAR scores range from 0 to 10; scores of 7 to 10 are considered normal. Min: minimum; max: maximum; APGAR: Appearance, Pulse, Grimace, Activity, Respiration. Table 1. Baseline characteristics of mothers and infants CONCLUSIONS • Using a highly sensitive and CZP-specific assay, CZP levels were below LLOQ (<0.032 µg/mL) in 13/14 infant blood samples at birth and in all infant blood samples at Weeks 4 and 8. • This indicates no to minimal placental transfer of CZP from mothers to infants, suggesting a lack of in utero fetal exposure during the third trimester. • No new safety signals were identified in the mothers. AEs experienced by the infants did not show any patterns or clusters of events suggesting a specific safety signal in children. • Combined with evidence from early exposure,10 these data support continuation of CZP treatment throughout pregnancy, if anti-TNF therapy is considered necessary. Figure 1. CRIB study design Figure 3. Plasma CZP concentrations in mothers and infants (n=14 mother-infant pairsa) a2/16 infants were excluded from the per protocol analysis set: 1 due to missing data at birth, and 1 due to implausible PK data at birth (i.e. data not consistent with a pediatric CZP PK model, based on the expected range of clearance, volume of distribution, and subsequent elimination half-life); b±24 hours; c±7 days (2 samples not collected); d±7 days. BLQ: below LLOQ (<0.032 µg/mL). OBJECTIVE • To accurately measure the level of placental transfer of certolizumab pegol (CZP) from mothers to infants using a highly sensitive CZP-specific assay. Lack of Placental Transfer of Certolizumab Pegol During Pregnancy: Results from CRIB, a Prospective, Postmarketing, Multicenter, Pharmacokinetic Study Alexa B. Kimball,1 Xavier Mariette,2 Bincy Abraham,3 Ann Flynn,4 Frauke Förger,5 Anna Moltó,6 René-Marc Flipo,7 Astrid van Tubergen,8 Laura Shaughnessy,9 Jeff Simpson,9 Marie Teil,10 Eric Helmer,11 Maggie Wang,9 Eliza Chakravarty12 1Harvard Medical Faculty Physicians at Beth Israel Deaconess Medical Center, Boston, MA; 2Université Paris-Sud, Le Kremlin-Bicêtre, France; 3Houston Methodist Hospital, Houston, TX; 4University of Utah, Salt Lake City, UT; 5University of Bern, Bern, Switzerland; 6Groupe Hospitalier Cochin, Paris, France; 7Centre Hospitalier Régional Universitaire de Lille, Lille, France; 8Maastricht University Medical Center, Maastricht, Netherlands; 9UCB Pharma, Raleigh, USA; 10UCB Pharma, Slough, UK; 11UCB Pharma, Brussels, Belgium; 12Oklahoma Medical Research Foundation, Oklahoma City, OK CZP Plasma Concentrations • In all mothers enrolled (n=16), CZP plasma levels at delivery were within the expected therapeutic range (median [range]: 24.4 [5.0–49.4] µg/mL). • Two infants were excluded from the per protocol analysis set: 1 due to missing data at birth, and 1 due to implausible PK data at birth (i.e. data not consistent with a pediatric CZP PK model, based on the expected range of clearance, volume of distribution, and subsequent elimination half-life). • Of the remaining 14 infants, 13 had no quantifiable CZP plasma levels at birth (<0.032 µg/mL); 1 infant had a minimal CZP level at birth of 0.042 µg/mL (infant/mother plasma ratio: 0.0009) (Figure 3). • None of the 14 infants had quantifiable CZP plasma levels at Weeks 4 and 8 (Figure 3). Of note, 9 of these infants were breastfed while their mothers were taking CZP. • Of the 16 umbilical cord samples, 1 was excluded due to missing data. Of the remaining 15 cords, 3 had quantifiable CZP levels (maximum: 0.048 µg/mL). Safety and Immunogenicity Analysis • AEs in the mothers were consistent with the known safety profile of CZP and pregnancy profile of these underlying diseases (Table 2). • Serious AEs (SAEs) in the mothers were mild to moderate, except one case of arrested labor and one case of prolonged labor. Six SAEs led to hospitalization; all were resolved except for delivery of a premature baby (Table 2). SULFO-TAG streptavidina Biotin-labeled anti-PEG antibody CZP TNF-coated electrode Fab' PEG 100 10 1 0.1 BLQ C Z P c o n c e n tr a ti o n ( µ g /m L ) Deliveryb Week 4c Week 8d LLOQ=0.032 µg/mL Mothers Infants • AEs experienced by the infants did not show any patterns or clusters of events suggesting a specific safety signal in children (Table 2). • Four SAEs were reported in two infants; all were mild to moderate except the infection. All SAEs were resolved (Table 2). • No anti-CZP antibodies were detected in the mothers, umbilical cords, or infants at any time point during the study. Home health nursing visits Screening Period Sampling Period Start of Pregnancy Birth 4 weeks (±7 days) postpartum Safety Follow-Up 8 weeks (±7 days) postpartum 5 weeks (±5 days) after final sample ≤35 days prior to deliverya Screening (≥30 weeks pregnant) CZP Dosing: = CZP 200 mg Q2W = CZP 400 mg Q4W Primary Endpoint: = Infant blood sampling (birth) Secondary Endpoint: = Cord blood sampling = Mother blood sampling Exploratory Endpoint: Infant blood sampling (4 and 8 weeks) = n=16N=21 aLast CZP dose given within 35 days prior to delivery. Q2W: every 2 weeks; Q4W: every 4 weeks. FC17PosterUCBPharmaKimballLackofPlacentalTransfer.pdf