POS0652 SEX DIFFERENCES IN THE EFFICACY AND SAFETY OF TOFACITINIB IN RHEUMATOID ARTHRITIS PATIENTS: A POST HOC ANALYSIS OF PHASE 3 AND LONG-TERM EXTENSION TRIALS
Authors: H. N. Jones, V. Strand, H. Schulze-Koops, E. Mysler, C. Kinch, D. C. Gruben, R. Germino, C. A. Connell, L. Eder
Journal: Annals of the Rheumatic Diseases (2021)

Background: Differences in efficacy outcomes favouring males vs females with rheumatoid arthritis (RA) have been reported with conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) and tumour necrosis factor inhibitors; results with Janus kinase inhibitors are less clear. Objectives: To assess the impact of sex on efficacy, safety and persistence in tofacitinib RA clinical trials. Methods: Efficacy and safety analyses included data pooled from Phase (P)3 randomised controlled trials (RCTs) of patients (pts) with RA and an inadequate response (IR) to methotrexate ( NCT00847613 ; NCT00853385 ) or ≥1 DMARD ( NCT00856544 ) who received tofacitinib 5 or 10 mg twice daily (BID), adalimumab (ADA) 40 mg Q2W or placebo (PBO), with background csDMARDs. Persistence analyses of pts receiving tofacitinib 5 or 10 mg BID ± csDMARDs used data pooled from two long-term extension trials ( NCT00661661 ; NCT00413699 ). Efficacy outcomes to Month (M)12 included: ACR20/50/70 responses, changes from baseline (Δ; BL) in DAS28-4(ESR), CDAI, HAQ-DI and FACIT-F, and DAS28-4(ESR) remission (&lt;2.6). Safety was evaluated to M24 for tofacitinib and ADA. Kaplan-Meier persistence analysis estimated time to discontinuation. Results: 2265 pts were included from P3 RCTs. Demographics and BL characteristics were comparable across sexes and treatments. Tofacitinib or ADA vs PBO generally led to significantly higher ACR20/50/70 responses in both sexes through M6. To M12, ACR20/50/70 responses were broadly comparable across active treatments and between sexes, with significant differences favouring males at some time points, including M3 (Figure 1). Statistically significant differences favouring males vs females were observed in DAS28-4(ESR) remission rates at most time points, including M3 (Figure 1); a similar trend was observed for ΔDAS28-4(ESR). ΔCDAI, ΔHAQ-DI and ΔFACIT-F significantly favoured males vs females receiving tofacitinib 5 mg BID at most time points, while ΔHAQ-DI and ΔFACIT-F tended to favour females receiving tofacitinib 10 mg BID. Rates of adverse events (AEs), serious AEs (SAEs), severe AEs and discontinuations due to AEs were slightly higher in females vs males with tofacitinib 5 mg BID; this was generally reversed with tofacitinib 10 mg BID and ADA (Table 1). AEs of special interest (AESI) were comparable between sexes with tofacitinib and ADA, although low event numbers limit interpretation (Table 1). Time to all-cause discontinuation and discontinuation due to AEs/lack of efficacy with tofacitinib 5 mg BID was similar between sexes. Numerical differences favouring females vs males were observed for time to all-cause discontinuation and discontinuation due to AEs with tofacitinib 10 mg BID. Table 1. Safety summary to M24 in pooled DMARD-IR P3 RCTs Tofacitinib 5 mg BID Tofacitinib 10 mg BID ADA Pts with events, n (% ) Females (N=707 ) Males (N=133 ) Females (N=698 ) Males (N=137 ) Females (N=162 ) Males (N=42 ) AEs 562 (79.5) 85 (63.9) 529 (75.8) 107 (78.1) 119 (73.5) 30 (71.4) SAEs 107 (15.1) 17 (12.8) 71 (10.2) 24 (17.5) 13 (8.0) 6 (14.3) Severe AEs 86 (12.2) 12 (9.0) 55 (7.9) 22 (16.1) 14 (8.6) 5 (11.9) Discontinuations due to AEs 87 (12.3) 10 (7.5) 88 (12.6) 10 (7.3) 17 (10.5) 5 (11.9) Death 6 (0.8) 4 (3.0) 0 3 (2.2) 1 (0.6) 2 (4.8) AESI Serious infections 28 (4.0) 6 (4.5) 27 (3.9) 6 (4.4) 2 (1.2) 1 (2.4) All HZ (non-serious/serious) 35 (5.0) 7 (5.3) 43 (6.2) 5 (3.6) 2 (1.2) 3 (7.1) MACE 5 (0.7) 0 2 (0.3) 3 (2.2) 0 3 (7.1) Malignancies (excl. NMSC) 7 (1.0) 1 (0.8) 9 (1.3) 1 (0.7) 0 1(2.4) NMSC 2 (0.3) 5 (3.8) 4 (0.6) 2 (1.5) 1 (0.6) 1 (2.4) Venous thromboembolism 3 (0.4) 0 3 (0.4) 1 (0.7) 0 0 HZ, herpes zoster; MACE, major adverse cardiovascular events; NMSC, non-melanoma skin cancer Conclusion: Efficacy outcomes with tofacitinib and ADA were generally higher in males and comparable in females vs previously reported mixed population response rates for advanced therapies. Safety findings did not reveal a consistent pattern between sexes. Tofacitinib persistence was similar between sexes. Acknowledgements: Study sponsored by Pfizer Inc. Medical writing support was provided by Christina Viegelmann, CMC Connect, and funded by Pfizer Inc. Disclosure of Interests: H Niall Jones Consultant of: Pfizer Inc, Vibeke Strand Consultant of: AbbVie, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion, Corrona, Eli Lilly, Galapagos, Genentech/Roche, Gilead, GlaxoSmithKline, Ichnos, Inmedix, Janssen, Kiniksa, Merck, Myriad Genetics, Novartis, Pfizer Inc, Regeneron, Samsung, Sandoz, Sanofi, Scipher, SetPoint Medical, UCB, Hendrik Schulze-Koops Consultant of: AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead Sciences, Hexal Sandoz, Hospira, Janssen-Cilag, MSD, Novartis, Pfizer Inc, Roche, UCB, Grant/research support from: Novartis, Pfizer Inc, Eduardo Mysler Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer Inc, Roche, Sanofi, Grant/research support from: Eli Lilly, Pfizer Inc, Roche, Cassandra Kinch Shareholder of: Pfizer Canada ULC, Employee of: Pfizer Canada ULC, David C Gruben Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Rebecca Germino Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Carol A. Connell Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Lihi Eder Speakers bureau: AbbVie, UCB, Consultant of: AbbVie, Celgene, Eli Lilly, Novartis, Pfizer Inc, UCB, Grant/research support from: AbbVie, Eli Lilly, Pfizer Inc, UCB