OP0273 CERTOLIZUMAB PEGOL TO PREVENT ADVERSE PREGNANCY OUTCOMES IN PATIENTS WITH ANTIPHOSPHOLIPID SYNDROME AND LUPUS ANTICOAGULANT (IMPACT): RESULTS OF A PROSPECTIVE, SINGLE ARM, OPEN-LABEL, PHASE 2 TRIAL

Background: Antiphospholipid syndrome (APS) is an autoimmune disorder associated with placenta-mediated adverse pregnancy outcomes (APO), including fetal death, preeclampsia, and fetal growth restriction, despite standard treatment with low molecular weight heparin (LMWH) plus low dose aspirin (LDA). Prior studies reported that the presence of lupus anticoagulant (LA) increases APO risk to rates greater than 40% [1]. Tumor necrosis factor-alpha (TNF-α) is a critical effector of placental dysfunction and fetal death in preclinical models of APS. In murine models of APS and non-autoimmune spontaneous preeclampsia, inhibition of TNF-α prevented fetal deaths and growth restriction and normalized placental size and structure [2, 3]. Objectives: The aim of this study is to evaluate whether certolizumab pegol, an Fc-free, pegylated Fab' fragment of a humanized TNF-α blocking monoclonal antibody with little or no transport across the placenta, reduces rates of APO in high-risk pregnancies with APS. Methods: In a single arm, open-label, phase 2 trial, we assessed treatment with certolizumab administered during gestational weeks' 8 through 28, in addition to LMWH and LDA, in pregnant patients with APS and LA. The primary APO was a composite of fetal death ≥10 weeks' gestation or preeclampsia with severe features or placental insufficiency requiring delivery <34 weeks' gestation. Target sample size was 45 participants with an expected APO rate of 20% with certolizumab versus 40% in historical controls from a prospectively-observed population of similar APS pregnancies managed with LMWH and LDA between 2003 and 2013. ClinicalTrials.gov: NCT03152058. Results: Between May 2017 and February 2024, 76 patients were screened for eligibility and 51 were enrolled. Forty-five (88%) met obstetric criteria for APS, 36 (71%) met thrombotic criteria for APS, and 30 (59%) met both. Ten (20%) patients had SLE. Among the 49 intent-to-treat (ITT) patients who had prior pregnancies, 43 (88%) had a history of a prior IMPACT APO. Collectively, these patients had 135 prior pregnancies, 87 of which were maintained beyond 10 weeks. Thirty-nine of these pregnancies treated with LMWH and LDA were maintained beyond 10 weeks, 27 (69%) of which resulted in an IMPACT APO, and 15 (38%) had live births with infants surviving to discharge. In IMPACT, Primary APO occurred in 9 of 45 patients (20%; 95% CI: 9.6%-34.6%) in the modified ITT population and 8 of 44 patients (18.2%; 95% CI: 8.2%-32.7%) in the per-protocol population meeting the pre-determined criteria for efficacy of certolizumab, and significantly lower than rates in historical control groups in the PROMISSE Study [4] (Figure 1). The median gestational age at delivery in all certolizumab-treated patients was 36.5 weeks and was after 30 weeks in those who met the primary outcome of preeclampsia. Neonatal survival to hospital discharge was 93%. There were no serious infections, and no new cases or severe flares of lupus. In exploratory analyses, we compared the most recent prior pregnancies treated with LMWH and LDA that progressed beyond 10 weeks with the patient's certolizumab-treated pregnancy (Figure 2, N=24). APO rates were 79% in the prior pregnancy vs 21% in IMPACT, (p<0.001), and the median gestational ages of delivery were 24.0 weeks versus 36.5 weeks, respectively (p<0.001). Furthermore, 8 of 24 (33%) prior pregnancies resulted in livebirths surviving to discharge compared to 20 of 24 (83%) in the subsequent certolizumab-treated pregnancies (p = 0.0002) (Figure 2). Conclusion: This is the first prospective treatment trial in pregnant patients using an immunomodulatory agent to prevent APOs. The study met pre-determined criteria for efficacy of certolizumab and suggests that the addition of certolizumab pegol treatment to standard of care regimen can improve pregnancy outcomes in APS patients. Studies to determine whether TNF-α blockade prevents placenta-mediated adverse outcomes in other at-risk populations are warranted. REFERENCES: [1] Buyon JP, Kim MY, Guerra MM, et al. Predictors of Pregnancy Outcomes in Patients With Lupus: A Cohort Study. Ann Intern Med 2015; 163(3): 153-63. [2] Berman J, Girardi G, Salmon JE. TNF-alpha is a critical effector and a target for therapy in antiphospholipid antibody-induced pregnancy loss. J Immunol 2005; 174(1): 485-90. [3] Gelber SE, Brent E, Redecha P, et al. Prevention of Defective Placentation and Pregnancy Loss by Blocking Innate Immune Pathways in a Syngeneic Model of Placental Insufficiency. J Immunol 2015; 195(3): 1129-38. [4] Lockshin MD, Kim M, Laskin CA, et al. Prediction of adverse pregnancy outcome by the presence of lupus anticoagulant, but not anticardiolipin antibody, in patients with antiphospholipid antibodies. Arthritis Rheum 2012; 64(7): 2311-8. Acknowledgements: National Institutes of Health, Lupus Foundation of America, and UCB, Inc. Disclosure of Interests: D. Ware Branch UCB Pharma, Mimi Kim: None declared, Marta Guerra: None declared, Joseph Worden: None declared, Carl Laskin: None declared, Maria DeSancho Pharmacosmos, Pharmacosmos, Inna Landres: None declared, Jason Knight: None declared, Haley Slosberg: None declared, Margaret Minett: None declared, Jane E. Salmon Pfizer, Johnson & Johnson, Bristol Myers Squib, Biogen, Eli Lilly, UCB Pharma, UCB Pharma. © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.

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